DE/$/$) 7,&0%,&0$&’ !&50/$% ./$8F’&/$+0 1+, /3 7,&/80/ +1 !&G+, … · 2016. 3. 30. · D"E"/$/$)" 7,&0%,&0$&’ !&50"/$% ./$8F’&/$+0 L,7!.M N :0/&,$+ 2"&’/3 7"%30+’+5-

!"#$%&' (#)$*+,- ."%,"/&,$&/!$0$*/,- +1 2"&'/3 &0# 4+0567",8 9&,"

:0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=> ?+'@ =A B+@ C

D"E"/$/$)" 7,&0*%,&0$&'!&50"/$% ./$8F'&/$+0 1+, /3"7,"&/8"0/ +1 !&G+,H"E,"**$)" H$*+,#",

(0 I)$#"0%"6J&*"# (0&'-*$*

KF0" ;<<=

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 2

!"##$%&$' ()&*&)+,

73$* ,"E+,/ *3+F'# O" %$/"# &* 1+''+P*Q

!"#$%&' (#)$*+,- ."%,"/&,$&/@ D"E"/$/$)" /,&0*%,&0$&' 8&50"/$% */$8F'&/$+0 1+, /3" /,"&/8"0/ +1 8&G+,#"E,"**$)" #$*+,#",Q &0 ")$#"0%"6O&*"# &0&'-*$*@ :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"*;<<=>=LCM@

-$./)%%)+, 0$1"$%&%

('' $0RF$,$"* ,"5&,#$05 E",8$**$+0 /+ ,"E,+#F%" &0- %+0/"0/ $0 /3" :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/.",$"* *3+F'# O" #$,"%/"# /+ !(.$01+@8+3S+0/&,$+@%&@

2+3 &+ 45&*), 6%%"$% ), &7$ 4,&*.)+ 2$*8&7 9$:7,+8+#; <%%$%%/$,& !$.)$%

('' ,"E+,/* $0 /3" :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* &," 1,""'- &)&$'&O'" $0 THU 1+,8&/ &/ /3"1+''+P$05 VD4Q PPP@3"&'/3@5+)@+0@%&W+3/&*@

T,$0/ %+E$"* %&0 O" +O/&$0"# O- %+0/&%/$05 !(.$01+@8+3S+0/&,$+@%&@

(+,=8):& += 6,&$.$%& !&*&$/$,&

('' &0&'-*"* $0 /3" :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* &," $8E&,/$&' &0# *FOG"%/ /+ & *-*/"8&/$%

")$#"0%"6O&*"# &**"**8"0/ E,+%"**@ 73"," &," 0+ %+8E"/$05 $0/","*/* +, %+01'$%/* +1 $0/","*/ /+ #"%'&,"@

-$$. 0$>)$3

('' !"#$%&' (#)$*+,- ."%,"/&,$&/ &0&'-*"* &," *FOG"%/ /+ "X/",0&' "XE",/ E"", ,")$"P@ (##$/$+0&''-A /3"

EFO'$% %+0*F'/&/$+0 E,+%"** $* &'*+ &)&$'&O'" /+ $0#$)$#F&'* P$*3$05 /+ %+88"0/ +0 &0 &0&'-*$* E,$+, /+1$0&'$Y&/$+0@ U+, 8+," $01+,8&/$+0A E'"&*" )$*$/

3//EQWWPPP@3"&'/3@5+)@+0@%&W"05'$*3WE,+)$#",*WE,+5,&8W+3/&%WEFO'$%Z"05&5"Z+)",)$"P@3/8'@

(+,&*:& 6,=+./*&)+,

73" !"#$%&' (#)$*+,- ."%,"/&,$&/!$0$*/,- +1 2"&'/3 &0# 4+0567",8 9&,"

;< HF0#&* ./,""/ ["*/A \</3 1'++,

7+,+0/+A :0/&,$+9(B(H(

!]^ ;B_I8&$'Q !(.$01+@8+3S+0/&,$+@%&

7"'"E3+0"Q =\_6`\=6\<a;

b..B \a\]6C`ac L:0'$0"M

b.JB aCc6\6=;=a6C;Ca6\ LTHUM

http://www.health.gov.on.ca/english/providers/program/ohtac/public_engage_overview.html

mailto:[email protected]


http://www.health.gov.on.ca/ohtas


D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 3

<5+"& &7$ ?$'):*8 <'>)%+.; !$:.$&*.)*&

73" !"#$%&' (#)$*+,- ."%,"/&,$&/ $* E&,/ +1 /3" :0/&,$+ !$0$*/,- +1 2"&'/3 &0# 4+0567",8 9&,"@ 73"

8&0#&/" +1 /3" !"#$%&' (#)$*+,- ."%,"/&,$&/ $* /+ E,+)$#" ")$#"0%"6O&*"# E+'$%- &#)$%" +0 /3"%++,#$0&/"# FE/&d" +1 3"&'/3 *",)$%"* &0# 0"P 3"&'/3 /"%30+'+5$"* $0 :0/&,$+ /+ /3" !$0$*/,- +1 2"&'/3

&0# 4+0567",8 9&," &0# /+ /3" 3"&'/3%&," *-*/"8@ 73" &$8 $* /+ "0*F," /3&/ ,"*$#"0/* +1 :0/&,$+ 3&)"&%%"** /+ /3" O"*/ &)&$'&O'" 0"P 3"&'/3 /"%30+'+5$"* /3&/ P$'' $8E,+)" E&/$"0/ +F/%+8"*@

73" !"#$%&' (#)$*+,- ."%,"/&,$&/ &'*+ E,+)$#"* & *"%,"/&,$&/ 1F0%/$+0 &0# ")$#"0%"6O&*"# 3"&'/3

/"%30+'+5- E+'$%- &0&'-*$* 1+, ,")$"P O- /3" :0/&,$+ 2"&'/3 7"%30+'+5- (#)$*+,- 9+88$//"" L:27(9M@

73" !"#$%&' (#)$*+,- ."%,"/&,$&/ %+0#F%/* *-*/"8&/$% ,")$"P* +1 *%$"0/$1$% ")$#"0%" &0# %+0*F'/&/$+0*

P$/3 "XE",/* $0 /3" 3"&'/3 %&," *",)$%"* %+88F0$/- /+ E,+#F%" /3" :0/&,$+ 2"&'/3 7"%30+'+5-(**"**8"0/ .",$"*@

<5+"& &7$ 4,&*.)+ 2$*8&7 9$:7,+8+#; <%%$%%/$,& !$.)$%

7+ %+0#F%/ $/* %+8E,"3"0*$)" &0&'-*"*A /3" !"#$%&' (#)$*+,- ."%,"/&,$&/ *-*/"8&/$%&''- ,")$"P* &)&$'&O'"

*%$"0/$1$% '$/",&/F,"A %+''&O+,&/"* P$/3 E&,/0",* &%,+** ,"'")&0/ 5+)",08"0/ O,&0%3"*A &0# %+0*F'/* P$/3

%'$0$%&' &0# +/3", "X/",0&' "XE",/* &0# 8&0F1&%/F,",*A &0# *+'$%$/* &0- 0"%"**&,- &#)$%" /+ 5&/3",$01+,8&/$+0@ 73" !"#$%&' (#)$*+,- ."%,"/&,$&/ 8&d"* ")",- "11+,/ /+ "0*F," /3&/ &'' ,"'")&0/ ,"*"&,%3A

0&/$+0&''- &0# $0/",0&/$+0&''-A $* $0%'F#"# $0 /3" *-*/"8&/$% '$/",&/F," ,")$"P* %+0#F%/"#@

73" $01+,8&/$+0 5&/3","# $* /3" 1+F0#&/$+0 +1 /3" ")$#"0%" /+ #"/",8$0" $1 & /"%30+'+5- $* "11"%/$)" &0#

*&1" 1+, F*" $0 & E&,/$%F'&, %'$0$%&' E+EF'&/$+0 +, *"//$05@ b01+,8&/$+0 $* %+''"%/"# /+ F0#",*/&0# 3+P &0"P /"%30+'+5- 1$/* P$/3$0 %F,,"0/ E,&%/$%" &0# /,"&/8"0/ &'/",0&/$)"*@ H"/&$'* +1 /3" /"%30+'+5-e*

#$11F*$+0 $0/+ %F,,"0/ E,&%/$%" &0# $0EF/ 1,+8 E,&%/$%$05 8"#$%&' "XE",/* &0# $0#F*/,- &## $8E+,/&0/$01+,8&/$+0 /+ /3" ,")$"P +1 /3" E,+)$*$+0 &0# #"'$)",- +1 /3" 3"&'/3 /"%30+'+5- $0 :0/&,$+@ b01+,8&/$+0

%+0%",0$05 /3" 3"&'/3 O"0"1$/*> "%+0+8$% &0# 3F8&0 ,"*+F,%"*> &0# "/3$%&'A ,"5F'&/+,-A *+%$&' &0# '"5&'$**F"* ,"'&/$05 /+ /3" /"%30+'+5- &**$*/ E+'$%- 8&d",* /+ 8&d" /$8"'- &0# ,"'")&0/ #"%$*$+0* /+ +E/$8$Y"

E&/$"0/ +F/%+8"*@

b1 -+F &," &P&," +1 &0- %F,,"0/ &##$/$+0&' ")$#"0%" /+ $01+,8 &0 "X$*/$05 ")$#"0%"6O&*"# &0&'-*$*A E'"&*"

%+0/&%/ /3" !"#$%&' (#)$*+,- ."%,"/&,$&/Q !(.$01+@8+3S+0/&,$+@%&@ 73" EFO'$% %+0*F'/&/$+0 E,+%"** $*&'*+ &)&$'&O'" /+ $0#$)$#F&'* P$*3$05 /+ %+88"0/ +0 &0 &0&'-*$* E,$+, /+ EFO'$%&/$+0@ U+, 8+," $01+,8&/$+0A

E'"&*" )$*$/ 3//EQWWPPP@3"&'/3@5+)@+0@%&W"05'$*3WE,+)$#",*WE,+5,&8W+3/&%WEFO'$%Z"05&5"Z+)",)$"P@3/8'@

@)%:8*)/$.73$* ")$#"0%"6O&*"# &0&'-*$* P&* E,"E&,"# O- /3" !"#$%&' (#)$*+,- ."%,"/&,$&/A :0/&,$+ !$0$*/,- +1 2"&'/3&0# 4+0567",8 9&,"A 1+, /3" :0/&,$+ 2"&'/3 7"%30+'+5- (#)$*+,- 9+88$//"" &0# #")"'+E"# 1,+8&0&'-*$*A $0/",E,"/&/$+0A &0# %+8E&,$*+0 +1 *%$"0/$1$% ,"*"&,%3 &0#W+, /"%30+'+5- &**"**8"0/* %+0#F%/"#O- +/3", +,5&0$Y&/$+0*@ b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d /3" !"#$%&' (#)$*+,- ."%,"/&,$&/ ["O*$/" 1+, & '$*/ +1 &''")$#"0%"6O&*"# &0&'-*"*Q 3//EQWWPPP@3"&'/3@5+)@+0@%&W+3/&*@

http://www.health.gov.on.ca/english/providers/program/ohtac/public_engage_overview.html

http://www.health.gov.on.ca/ohtas


D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 4

Table of Contents

TABLE OF CONTENTS ............................................................................................................................................4

ABBREVIATIONS......................................................................................................................................................6

GLOSSARY .................................................................................................................................................................7

EXECUTIVE SUMMARY .........................................................................................................................................8

OBJECTIVE .................................................................................................................................................................8THE TECHNOLOGY .....................................................................................................................................................8REVIEW STRATEGY ....................................................................................................................................................8SUMMARY OF FINDINGS .............................................................................................................................................8CONCLUSION ............................................................................................................................................................11

OBJECTIVE..............................................................................................................................................................11

BACKGROUND........................................................................................................................................................11

CLINICAL NEED – TARGET POPULATION AND CONDITION .......................................................................................11EXISTING TREATMENT OPTIONS OTHER THAN TECHNOLOGY BEING REVIEWED.....................................................12Treatment-Resistant or Refractory Depression ...................................................................................................13

NEW TECHNOLOGY BEING REVIEWED: REPETITIVE MAGNETIC TRANSCRANIAL

STIMULATION ........................................................................................................................................................14

REGULATORY STATUS..............................................................................................................................................16

LITERATURE REVIEW ON EFFECTIVENESS.................................................................................................17

OBJECTIVE ...............................................................................................................................................................17QUESTIONS ASKED...................................................................................................................................................17METHODS.................................................................................................................................................................17Inclusion criteria .................................................................................................................................................17

Exclusion criteria ................................................................................................................................................18

Intervention..........................................................................................................................................................18

Literature Search.................................................................................................................................................18

Outcomes of Interest ............................................................................................................................................18

RESULTS OF LITERATURE REVIEW ON EFFECTIVENESS ............................................................................................18Summary of Existing Health Technology Assessments ........................................................................................18

Cochrane Systematic Review...............................................................................................................................19

Description of the Scales .....................................................................................................................................20

Comparisons With Electroconvulsive Therapy....................................................................................................42

Summary of Medical Advisory Secretariat Review..............................................................................................47

Statistical Analysis...............................................................................................................................................48

Mood Ratings.......................................................................................................................................................48

Working Memory – Letter Numbering (LN) Sequencing .....................................................................................49

New Learning – Acquisition ................................................................................................................................49

New Learning – Retention ...................................................................................................................................50

New Learning – Retrograde Memory ..................................................................................................................50

SUMMARY OF FINDINGS.....................................................................................................................................67

LIMITATIONS ............................................................................................................................................................68Biased randomization ..........................................................................................................................................68

Patient variability between studies ......................................................................................................................69

Dropouts or withdrawals.....................................................................................................................................69

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 5

Measurement of treatment outcomes using scales or inventories........................................................................69

Placebo effect ......................................................................................................................................................70

Short-term studies................................................................................................................................................70

Clinical versus statistical significance ................................................................................................................70

Clinical/methodological diversity and statistical heterogeneity..........................................................................71

ECONOMIC ANALYSIS .........................................................................................................................................71

LITERATURE REVIEW ...............................................................................................................................................71ONTARIO-BASED ECONOMIC ANALYSIS...................................................................................................................71

EXISTING GUIDELINES FOR USE OF TECHNOLOGY .................................................................................72

APPRAISAL ..............................................................................................................................................................75

POLICY CONSIDERATIONS ........................................................................................................................................75Patient outcomes..................................................................................................................................................75

Demographics......................................................................................................................................................76

Diffusion ..............................................................................................................................................................76

Cost......................................................................................................................................................................76

Stakeholder Analysis............................................................................................................................................77

System Pressures .................................................................................................................................................77

APPENDICES............................................................................................................................................................78

APPENDIX 1 ..............................................................................................................................................................78APPENDIX 2 ..............................................................................................................................................................79APPENDIX 3 ..............................................................................................................................................................80

REFERENCES ..........................................................................................................................................................95

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 6

Abbreviations

ANCOVA Analysis of covarianceANOVA Analysis of varianceBDI Beck Depression InventoryBPRS Brief Psychiatric Rating ScaleCGI Clinical Global Impression ScaleCI Confidence intervalDSM-IV Diagnostic and Statistical Manual of Mental Disorders IVECT Electroconvulsive therapyDLPFC Dorsolateral prefrontal cortexGAF Global Assessment of FunctionGAS Global Assessment ScaleGDR Global Depression ScaleHDRS Hamilton Depression Rating ScaleHz HertzLDLPFC Left dorsolateral prefrontal cortexMADRS Montgomery-Asberg Depression Rating ScaleMDD Major depressive disorderMMSE Mini-Mental State ExaminationPET Positron emission tomographyPSQI Pittsburg Sleep Quality IndexRPFC Right prefrontal cortexrTMS Repetitive transcranial magnetic stimulationSD Standard deviationSMD Standardized mean differenceTMS Transcranial magnetic stimulationWMD Weighted mean differenceYMRS Young Mania Rating Scale

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 7

Glossary

Dorsal: Denoting a position more toward the back surface than some other object of reference.

Electroconvulsive therapy (ECT): Psychiatric treatment that briefly passes an electrical current throughthe brain in order to produce a convulsion. Treatment can be delivered bilaterally (electrodes placed onboth sides of the skull) or unilaterally (on the right side of the skull).

Hertz (Hz): Unit of frequency.

Lateral: Denoting a position farther from the median plane or midline of the body or of a structure.

Prefrontal cortex: The anterior part of the frontal cortex of the brain.

Recovery: Remission for at least 6 consecutive months.

Regression to the mean: Occurs whenever a nonrandom sample is selected from a population and 2imperfectly correlated variables are measured such as 2 consecutive blood pressure measurements. Itoccurs whenever a group is selected with extreme values for one variable and another variable is thenmeasured.

Remission: Attainment of a virtually asymptomatic status (e.g., HRSD score < 7) for at least 2consecutive weeks.

Repetitive transcranial magnetic stimulation: The application of pulsed magnetic fields to the corticalsurface of the brain with the aim of stimulating or disrupting ongoing brain activity.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 8

Executive Summary

Objective

This review was conducted to assess the effectiveness of repetitive transcranial magnetic stimulation(rTMS) in the treatment of major depressive disorder (MDD).

The Technology

rTMS is a noninvasive way to stimulate nerve cells in areas of the brain. During rTMS, an electricalcurrent passes through a wire coil placed over the scalp. The current induces a magnetic field thatproduces an electrical field in the brain that then causes nerve cells to depolarize, resulting in thestimulation or disruption of brain activity.

Researchers have investigated rTMS as an option to treat MDD, as an add-on to drug therapy, and, inparticular, as an alternative to electroconvulsive therapy (ECT) for patients with treatment-resistantdepression.

The advantages of rTMS over ECT for patients with severe refractory depression are that generalanesthesia is not needed, it is an outpatient procedure, it requires less energy, the simulation is specificand targeted, and convulsion is not required. The advantages of rTMS as an add-on treatment to drugtherapy may include hastening of the clinical response when used with antidepressant drugs.

Review Strategy

The Medical Advisory Secretariat used its standard search strategy to locate international healthtechnology assessments and English-language journal articles published from January 1996 to March2004.

Summary of Findings

Some early meta-analyses suggested rTMS might be effective for the treatment of MDD (for treatment-resistant MDD and as an add-on treatment to drug therapy for patients not specifically defined astreatment resistant). There were, however, several crucial methodological limitations in the includedstudies that were not critically assessed. These are discussed below.

Recent meta-analyses (including 2 international health technology assessments) have done evidence-based critical analyses of studies that have assessed rTMS for MDD. The 2 most recent health technologyassessments (from the Oxford Cochrane Collaboration and the Norwegian Centre for Health TechnologyAssessment) concluded that there is no evidence that rTMS is effective for the treatment of MDD, eitheras compared with a placebo for patients with treatment-resistant or nontreatment-resistant MDD, or as analternative to ECT for patients with treatment-resistant MDD. This mainly due to the poor quality of thestudies.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 9

The major methodological limitations were identified in older meta-analyses, recent health technologyassessments, and the most recently published trials (Level 2–4 evidence) on the effectiveness of rTMS forMDD are discussed below.

Small sample size was a limitation acknowledged by many of the authors. There was also a lack of apriori sample size calculation or justification.

Biased randomization may have been a problem. Generally, the published reports lacked detailedinformation on the method of allocation concealment used. This is important because it is impossible todetermine if there was a possible influence (direct or indirect) in the allocation of the patients to differenttreatment groups.

The trials were single blind, evaluated by external blinded assessors, rather than double blind.Double blinding is more robust, because neither the participants nor the investigators know whichparticipants are receiving the active treatment and which are getting a placebo. Those administeringrTMS, however, cannot be blinded to whether they are administering the active treatment or a placebo.

There was patient variability among the studies. In some studies, the authors said that patients were“medication resistant,” but the definitions of resistant, if provided, were inconsistent or unclear. Forexample, some described “medication resistant” as failing at least one trial of drugs during the currentdepressive episode. Furthermore, it was unclear if the term “medication resistant” referred toantidepressants only or to combinations of antidepressants and other drug augmentation strategies (suchas neuroleptics, benzodiazepine, carbamazepine, and lithium). Also variable was the type of depression(i.e., unipolar and/or bipolar), if patients were inpatients or outpatients, if they had psychotic symptoms orno psychotic symptoms, and the chronicity of depression.

Dropouts or withdrawals were a concern. Some studies reported that patients dropped out, but providedno further details. Intent-to-treat analysis was not done in any of the trials. This is important, becauseignoring patients who drop out of a trial can bias the results, usually in favour of the treatment. This isbecause patients who withdraw from trials are less likely to have had the treatment, more likely to havemissed their interim checkups, and more likely to have experienced adverse effects when taking thetreatment, compared with patients who do not withdraw. (1)

Measurement of treatment outcomes using scales or inventoriesmakes interpreting results anddrawing conclusions difficult. The most common scale, the Hamilton Depression Rating Scale (HDRS) isbased on a semistructured interview. Some authors (2) reported that rating scales based on semistructuredinterviews are more susceptible to observation bias than are self-administered questionnaires such as theBeck Depression Inventory (BDI). Martin et al. (3) argued that the lack of consistency in effect asdetermined by the 2 scales (a positive result after 2 weeks of treatment as measured by the HDRS and anegative result for the BDI) makes definitive conclusions about the nature of the change in mood ofpatients impossible. It was suggested that because of difficulties interpreting results from psychometricscales, (4) and the subjective or unstable character of MDD, other, more objective, outcome measuressuch as readmission to hospital, time to hospital discharge, time to adjunctive treatment, and time offwork should be used to assess rTMS for the treatment of depression.

A placebo effect could have influenced the results. Many studies reported response rates for patientswho received placebo treatment. For example, Klein et al. (5) reported a control group response rate ashigh as 25%. Patients receiving placebo rTMS may receive a small dose of magnetic energy that mayalter their depression.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 10

Short-term studies were the most common. Patients received rTMS treatment for 1 to 2 weeks. Moststudies followed-up patients for 2 to 4 weeks post-treatment. Dannon et al. (6) followed-up patients whoresponded to a course of ECT or rTMS for up to 6 months; however, the assessment procedure was notblinded, the medication regimen during follow-up was not controlled, and initial baseline data for thepatient groups were not reported. The long-term effectiveness of rTMS for the treatment of depression isunknown, as is the long-term use, if any, of maintenance therapy. The cost-effectiveness of rTMS for thetreatment of depression is also unknown. A lack of long-term studies makes cost-effectiveness analysisdifficult.

The complexity of possible combinations for administering rTMS makes comparing like with likedifficult. Wasserman and Lisanby (7) have said that the method for precisely targeting the stimulation inthis area is unreliable. It is unknown if the left dorsolateral prefrontal cortex is the optimal location fortreatment. Further, differences in rTMS administration include number of trains per session, duration ofeach train, and motor threshold.

Clinical versus statistical significance. Several meta-analyses and studies have found that the degree oftherapeutic change associated with rTMS across studies is relatively modest; that is, results may bestatistically, but not necessarily clinically, significant. (8-11). Conventionally, a 50% reduction in theHDRS scores is commonly accepted as a clinically important reduction in depression. Although somestudies have observed a statistically significant reduction in the depression rating, many have not showsthe clinically significant reduction of 50% on the HDRS. (11-13) Therefore, few patients in these studieswould meet the standard criteria for response. (9)

Clinical/methodological diversity and statistical heterogeneity. In the Norwegian health technologyassessment, Aarre et al. (14) said that a formal meta-analysis was not feasible because the designs of thestudies varied too much, particularly in how rTMS was administered and in the characteristics of thepatients. They noted that the quality of the study designs was poor. The 12 studies that comprised theassessment had small samples, and highly variable inclusion criteria and study designs. The patients’previous histories, diagnoses, treatment histories, and treatment settings were often insufficientlycharacterized. Furthermore, many studies reported that patients had treatment-resistant MDD, yet did notlistclear criteria for the designation. Without this information, Aarre and colleagues suggested that theinterpretation of the results is difficult and the generalizability of results is questionable. They concludedthat rTMS cannot be recommended as a standard treatment for depression: “More, larger and morecarefully designed studies are needed to demonstrate convincingly a clinically relevant effect of rTMS.”

In the Cochrane Collaboration systematic review, Martin et al. (3;15) said that the complexity of possiblecombinations for administering rTMS makes comparison of like versus like difficult. A statistical test forheterogeneity (chi-square test) examines if the observed treatment effects are more different from eachother than one would expect due to random error (or chance) alone. (16) However, this statistical testmust be interpreted with caution because it has low power in the (common) situation of a meta-analysiswhen the trials have small sample sizes or are few. This means that while a statistically significant resultmay indicate a problem with heterogeneity, a nonsignificant result must not be taken as evidence of noheterogeneity.

Despite not finding statistically significant heterogeneity, Martin et al. reported that the overall meanbaseline depression values for the severity of depression were higher in the treatment group than in theplacebo group. (3;15) Although these differences were not significant at the level of each study, they mayhave introduced potential bias into the meta-analysis of pooled data by accentuating the tendency forregression to the mean of the more extreme values. Individual patient data from all the studies were notavailable; therefore, an appropriate adjustment according to baseline severity was not possible. Martin etal. concluded that the findings from the systematic review and meta-analysis provided insufficient

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 11

evidence to suggest that rTMS is effective in the treatment of depression. Moreover, there were severalconfounding factors (e.g., definition of treatment resistance) in the studies, thus the authors concluded,“The rTMS technique needs more high quality trials to show its effectiveness for therapeutic use.”

Conclusion

Due to several serious methodological limitations in the studies that have examined the effectiveness ofrTMS in patients with MDD, it is not possible to conclude that rTMS either is or is not effective as atreatment for MDD (in treatment-resistant depression or in nontreatment-resistant depression).

Objective

The primary objective was to perform an evidence-based analysis of the effectiveness and cost-effectiveness of rTMS for the treatment of major depressive disorder.

Background

Clinical Need – Target Population and Condition

Mood disorders are characterized by a disturbance in the regulation of mood, behaviour, and affect.Mood disorders are subdivided into depressive disorders, bipolar disorders, and depression associatedwith medical illness or alcohol and substance abuse. (17) Depressive disorders are differentiated frombipolar disorders by the absence of a manic or hypomanic episode.

Major depressive disorder (MDD) is defined as depressed mood on a daily basis for a minimum of 2weeks. An episode may be characterized by sadness, indifference, apathy, or irritability. It is usuallyassociated with changes in sleep patterns, appetite, and weight; motor agitation or retardation; fatigue;impairment in concentration and decision making; feelings of shame or guilt; and thoughts of death ordying. (17)

MDD frequently follows a recurrent or chronic course and impairs quality of life considerably. By 2020,the World Health Organization predicts that major depression will be second only to ischemic heartdisease as a cause of disability, ahead of common health problems such as infectious diseases, cancer, andaccidents. (18)

The average age of onset of MDD ranges from the early 20s to the early 30s. Major depression isincreasingly recognized as primarily a chronic and recurrent disease with frequent episode relapses andrecurrences. (18) Recovery (i.e., symptom remission) occurs in about 50% of men and women after 1year. However, recurrence of depressive episodes in people who recover from an index episode of majordepression is extremely common. As many as 85% of people who have recovered from MDD haveanother episode within 15 years, as do 58% of people who remain well for at least 5 years after recovery.(18;19)

Predictors of recurrence include female sex, a longer depressive episode before treatment, more priorepisodes, and never marrying. (19) Risk of recurrence tends to decrease as the length of time a person has

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 12

remained well increases. People hospitalized for a first episode of depression have a 50% lifetime risk ofreadmission, and those who have had previous hospitalizations have a 50% risk of readmission within thenext 3 years after discharge. (18-20)

In Ontario, an expert consultant estimated that about 6% to 7% of the population has experienced anepisode of major depression the last year. About 50% of these people will have recurrent depression (therest will have 1 or 2 lifetime episodes only). Of the 50% with recurrent depression, about 25% will notrespond to at least 2 medications; therefore, they will be considered resistant. This means about 0.8% ofthe population (96,000 people per year if the population is 12 million) has had an episode of treatment-resistant depression in the past year.

Of these, 80% would not have been considered for electroconvulsive therapy (ECT), the gold standard fortreatment-resistant depression, for the following reasons:

! Anesthetic contraindications! Unavailability of ECT! Unavailability of inpatient facilities! Requested an alternative antidepressant treatment

About 10% of these people would be eligible for and accept a course of ECT in 1 year (about 1,800patients). It is estimated that close to 10% of these patients may have also received ECT in the past,leaving about 1,500 new patients who may have received ECT in 1 year.

Existing Treatment Options Other Than Technology Being Reviewed

Treatment requires coordinating short-term symptom remission with longer-term maintenance strategiesdesigned to prevent recurrence. According to the American Psychiatric Association guidelines, (21)treatment for MDD may include the following:

! Drug therapy (e.g., selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamineoxidase inhibitors, venlafaxine, bupropion, mirtazapine, buspirone, pindolol, noradrenergic tricyclicagents, alpha 2 antagonists, atypical antipsychotics, thyroid augmentation, and lithium). Duringtreatment, positive response to antidepressant medication should be evident to some degree by 4weeks, with full response by 8 to 12 weeks. (22) Patients with depression that has not respondedpositively by 4 weeks should be re-evaluated. The diagnosis should be reconsidered, the patient’sadherence to medication should be assessed, or adjunctive psychotherapy should be considered.Usually, some sort of further intervention is required. Strategies for patients whose depression doesnot respond to a given drug after 4 weeks include switching to a different antidepressant, adding asecond antidepressant, or augmenting therapy with a drug such as lithium. (22)

! Psychotherapy! Drug therapy plus psychotherapy! ECT

ECT is an established treatment for severe, incapacitating forms of treatment-refractory depression. (17)During ECT, an electric current is passed through the brain by electrodes that have been placed on thescalp. This induces generalized seizure activity. During the procedure, the patient is placed under generalanesthetic and given muscle relaxants to prevent body spasms. ECT electrodes are placed on one or bothsides of the head. Unilateral placement is usually on the nondominant side of the brain to reduce adversecognitive effects. The number of sessions in a course of ECT ranges from 6 to 12. ECT is usuallyadministered twice a week. It is rarely given as continuation or maintenance therapy to prevent the relapseof symptoms, and it can be either an inpatient or an outpatient procedure.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 13

A systematic review and meta-analysis of the efficacy and safety of ECT to treat depressive disorders wasconducted by the United Kingdom ECT Review Group. (23) Although many of the trials were old, andmost were small, the evidence revealed that in the short-term (i.e., at the end of a course of treatment),ECT is an effective treatment for adult patients who have depressive disorders and no substantialcormorbidity.

Rose et al. (24) did a descriptive systematic review of physician- and patient-led research to examinepatients’ views on the benefits of, and possible memory loss from, ECT. Although the various studies didnot use consistent definitions or standardized ratings for memory loss, Rose et al. concluded that one-thirdof patients reported experiencing memory loss after ECT.

The management of depression in patients with bipolar depression differs in some important aspects fromthose with unipolar depression. For example, antidepressants are used more cautiously, in case theytrigger a manic relapse. Also, a manic relapse may lead to an apparent “improvement” in depressionscores and assessment. Finally, most patients with established bipolar disorder are also taking a moodstabilizer, such as lithium. (25)

Treatment-Resistant or Refractory Depression

The term refractory depression does not distinguish among treatment resistance, chronicity, relapse, orrecurrence and it does not account for psychosocial factors that may prevent recovery. (25) Moreover, theterm does not take into account if the patient has had an adequate course of (or any) psychotherapy.

In 2002, Stimpson et al. (26) systematically reviewed randomized controlled trials (RCTs) that assessedthe efficacy of a pharmacological or psychological intervention for treatment-refractory depression.Inclusion criteria were RCTs that included adults aged 18 to 75 years, with a diagnosis of unipolardepression, and who had not responded to a 4-week course of a recommended dose of an antidepressant.

They identified 16 RCTs. The strategy that had received the most investigation was augmentation ofexisting antidepressant medication. There were no studies of psychological treatment. It was possible todo a meta-analysis using the results from 2 trials that investigated lithium and 3 that studied pindolol. Allthe trials were too small to detect an important clinical response. The authors concluded that treatment-refractory depression is a common clinical problem. Furthermore, they noted that the lack of evidence oneffectiveness is reflected by an absence of consensus among clinicians and in the vagueness of currentguidelines.

A limitation to this study was that treatment-resistant depression was defined according to the 1974World Psychiatric Association definition, which used a 4-week criterion. Importantly, most otherdefinitions of treatment resistance require patients to have failed to respond to more than a single courseof antidepressants. (27)

Up to now, there has been little guidance on the management of treatment-refractory depression. (28)Current guidelines suggest increasing the dose of antidepressants, switching to a different class ofantidepressants, adding psychotherapy, or augmenting antidepressant therapy with lithium or ECT.Stimpson et al. (26) argued that the lack of guidance is reflected by variation in the management oftreatment-refractory depression. They supported their argument by stating the following:

! One-third of psychiatrists in the Northeastern United States preferred lithium augmentation. (29)! Canadian psychiatrists had an equal preference for a second tricyclic antidepressant, augmentation

with a monoamine oxidase inhibitor, and augmentation with lithium. (28)

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 14

! The most popular choice in the United Kingdom was to increase the dose or to change the class ofantidepressant. However, 39% of respondents in that study said they were not confident whentreating this condition. (30)

Thase and Rush (27) estimated that 60% to 70% of patients able to tolerate an antidepressant will respondto their drug of first choice, and 5% to 10% will remain depressed despite multiple interventions. Thispoorly responsive group has been variously described as resistant, refractory, or intractable in theliterature. Thase and Rush proposed that the term “treatment resistance” be clarified by a stage as shownin Table 1:

Table 1: Stage of Treatment Response in Clinical Depression*Stage Treatment Response

0 Has not had a single adequate trial of medication

1 Nonresponse to an adequate trial of one medication (monotherapy)

2 Failure to respond to two different adequate monotherapy trials of medicationswith different pharmacological profiles (e.g., TCA and SSRI) †

3 Stage 2 plus failure to respond to one augmentation strategy (e.g., lithium orthyroid augmentation of one of the monotherapies)

4 Stage 3 plus a failure on a second augmentation strategy

5 Stage 4 plus failure to respond to ECT†

* Thase and Rush (27)†TCA represents tricyclic antidepressants; SSRI, selective serotonin reuptake inhibitors; ECT,electroconvulsive therapy

New Technology Being Reviewed: Repetitive

Magnetic Transcranial Stimulation

Transcranial magnetic stimulation (TMS) is a noninvasive way to stimulate nerve cells in areas of thebrain. During TMS, an electrical current passes through a wire coil placed over the scalp (Figures 1 and 2in Appendix 1). The current induces a magnetic field that produces an electrical field in the brain, whichthen causes nerve cells to depolarize, resulting in the stimulation or disruption of brain activity. (31)

TMS can be applied once or repeated many times per second with variation in intensity, site, andorientation of the magnetic field. In most studies, figure-8 coils are used (Figure 2 in Appendix 1). (31)Figure-8 coils are 2 round coils that, when placed side by side, produce a focal stimulation. Coils with asmaller diameter have a more focused field of stimulation but require greater stimulation intensity toproduce similar depth-of-field penetration. Fitzgerald et al. (31) have said that highly focused stimulationis essential for many research applications, although it is unclear if this property will prove of use inclinical situations where less focused stimulation may better compensate for variations in diseaselocalization and differences in anatomy among people.

The frequency of cortical stimulation varies. Rapid-rate or repetitive TMS (rTMS) usually refers to theapplication of TMS for a train of minutes at frequencies above 1 Hertz (Hz) and is commonly used intreatment studies. TMS at less than or equal to 1Hz is referred to as slow or low-frequency TMS. Hasey(32) has suggested that the ability to stimulate the brain either at either high or low frequency isimportant, because high-frequency rTMS (e.g., 20 Hz) may increase cerebral blood flow and neuronalexcitability in the region of the cortex under the coil, but low-frequency rTMS (less than or equal to1Hz)may have the opposite effect.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 15

The magnetic pulse is further described by its intensity in proportion to the motor threshold of theindividual. The motor threshold is the lowest intensity of stimulation that, when applied to the motorcortex, causes a standard contraction of a muscle in at least 5 of 10 consecutive trials. (9) When rTMS isadministered, the number of pulse trains per daily session is usually described, as are the intertraininterval, the number of daily sessions, the site of stimulation, the type of coil used, and the orientation ofthe coil relative to the site on the scalp. (9)

Fitzgerald et al. (31) noted that the design and subsequent interpretation of therapeutic trials using TMSmay be complicated by confounding variables such as the following:

! Prior response to medication therapies! Current medication therapy! Illness duration! Severity! Treatment location (i.e., on an inpatient or outpatient basis)! Diagnosis! Intensity, frequency, and location of stimulation! Number of stimuli applied in each train of stimulation! Number of trains per session

Fitzgerald and colleagues also noted that many studies have been done based on 5-days-per-weekstimulation, although this choice appears to have arisen out of convenience rather than a provenadvantage. Patients receiving rTMS are usually fully awake and sitting. Sessions can last from 20 minutesto 1 hour. (9)

The control subjects in TMS studies may also present a problem. In crossover research designs, a scalpmuscle effect with placebo stimulation may compromise the blind condition. (31) Ideally, a placebo forTMS provides scalp and nose sensation but has minimal cortical stimulation. However, the higher thedegree of sensation achieved, the higher the likelihood of cortical stimulation.

In 1994, it was suggested that the prefrontal cortex may be an effective target area of the brain for TMS(Figures 3 and 4 in Appendix 2). This brain region was selected because of evidence of an associationbetween the response to ECT and changes in prefrontal cortex function, and because authors of imagingstudies had reported abnormalities in the prefrontal cortex in patients with depression. (31)

rTMS has been most studied in the left prefrontal cortex (Figure 4 in Appendix 2). More recently, therehas been interest in the therapeutic effects of slow TMS administered to the right prefrontal cortex. Someresearchers have speculated that rTMS boosts underlying activity levels (e.g., increasing activity on theleft in depression and on the right in mania), whereas slow TMS decreases underlying activity levels(thereby reducing a relative hyperactivity on the right side in depression). (31)

The method to determine the location of the left dorsolateral prefrontal cortex (LDLPFC) was introducedby George et al. (33) It involves determining the optimal site of stimulation over the motor cortex to elicitmotor evoked potentials in the abductor pollicus brevis the thumb muscle). The coil is then moved 5 cmforward on the parasagittal plane. It is then presumed to be over the dorsolateral prefrontal cortex(DLPFC). The magnetic stimulus intensity for the treatment is typically set as a percentage of the motorthreshold. As noted, Burt et al. (9) have argued that this method is inexact, because it does not account forindividual differences in brain size and anatomy. In basic science research, magnetic resonance imaging-guided 3-dimensional stereotactic methods have been used to provide more precise coil positioningrelative to specific anatomic locations, but this technique has not been used in many therapeutic trials. (9)

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 16

To date, there is a presumption of a strong association between the motor threshold and the intensityneeded to produce the physiological response in the DLPFC using rTMS. (9) Because the cortex-to-coildistance is the major determinant of local induced current density and has shown a relationship to themotor threshold, factors such as cortical atrophy may introduce variability in the distance between the coiland the motor cortex and the coil and the DLPFC. Originally, the use of the motor threshold to determinethe intensity of stimulation over the DLPFC was introduced as a safety precaution, (34) because highlyintense rTMS elicited seizures in a few healthy volunteers.

Potential clinical uses of rTMS may be as an add-on to drug therapy and as a replacement for ECT forpatients who have treatment-resistant MDD. Possible advantages of rTMS as an add-on to drug treatmentmay be a hastened clinical response in conjunction with antidepressants. The advantages of rTMS overECT for patients with treatment-resistant depression may include the following:

! No general anesthesia is given.! It is an outpatient procedure.! The energy requirement is lower. Hair, skin, and skull are not good electrical conductors; therefore,

to reach brain tissue, large currents must pass through skin-surface electrodes during ECT. However,the skull and other tissues are more “transparent” to the magnetic field created by a TMS coil, andlower energy is needed to alter neuronal activity. (32) Also, as some researchers have noted, “themagnetic field can be highly focused, thereby reducing the side effects caused by the large currentsthat probably flow diffusely through neuronal structures during ECT.” (32)

! There is no social stigma of having to receive ECT. (35)! The stimulation is specific and targeted.! Convulsion is not part of the procedure.! There are minimal adverse effects, such as mild headache and discomfort at the site of stimulation.! There are no known adverse effects on cognition.

Regulatory Status

The following TMS devices are licensed by Health Canada:

! Multipulse Cortical Stimulator (Digitmer Limited, Welwyn Garden City, United Kingdom). This is aClass 2 device(Licence 6887) indicated by Health Canada for “transcranial stimulation with trains ofelectrical shock permit rapid assessment of the functional continuity of the motor pathways.”

Digitimer’s Web site states that that the Multipulse cortical stimulator is considered “transcranialelectrical stimulation” and a “safe and efficient transcranial cortical (electrical) motor evoked potential(TceMEP) generation for effective spinal cord monitoring.” In addition, it states, “TceMEPs are nowused worldwide during intraoperative spinal cord monitoring to help prevent postoperative paraplegia andour unique D185 Multipulse stimulator is the only stimulator cleared by the FDA for this application.”

Another company in the United Kingdom, The Magstim Company Limited (Whitland, Carmarthenshire,Wales), makes 3 devices that are licensed by Health Canada for use as: “A nerve stimulator. Intended forthe assessment of neuromuscular function.” They are as follows:

! Magstim Rapid (Class 2; licence 62504).! Magstim Model 200 2 (Class 2; licence 62505).! Magstim Model 200 (Class 2; licence 62506).

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 17

Also overseas, Medtronic A/S (Charlottenlund, Denmark) makes the following devices that are licensedby Health Canada:

! Magpro Magnetic Stimulator (Class 3; licence 7355). This is indicated by Health Canada for use as“magnetic stimulation of the central nervous system.”

! Magpro X100 Series (Class 3; licence 60608). This is indicated by Health Canada for use as: “Anon-invasive way of stimulating nerves in the central and peripheral nervous system. Used short-termto examine the physiology of the motor pathways, functional aspects of motor nerves stimulation,human cortical physiology, to change muscle function in a therapeutic manner and to change brainactivity in a therapeutic manner.”

! Maglite Magnetic Stimulator (Class 3; licence 12164). This is indicated by Health Canada for use as“magnetic stimulation of the central nervous system.”

! According to the Medtronic product monograph for Magpro, the indication for its use states, “It isalso intended for investigating the effects of rTMS.”

As of this review, no device using cortical magnetic stimulation to treat refractory MDD has beenapproved for use in the United States by the United States Food and Drug Administration.

Literature Review on Effectiveness

Objective

! To assess the effectiveness and cost-effectiveness of rTMS for MDD.

Questions Asked

! Is rTMS more effective than a placebo for treatment-resistant MDD?! Is rTMS more effective or as effective as ECT for treatment-resistant MDD?! What adverse effects are associated with rTMS treatment?! Is rTMS (with or without drugs or psychotherapy) more effective than only drugs or psychotherapy

for the treatment of MDD?

Methods

Inclusion criteria

! English-language articles (January 1996–March 2004)! Journal articles that report primary data on the effectiveness or cost-effectiveness of rTMS obtained

in a clinical setting, or analysis of primary data maintained in registries or databases! Study design and methods that are clearly described! Systematic reviews, RCTs, non-RCTS or cohort studies that have >20 patients, and cost-effectiveness

studies

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 18

Exclusion criteria

! Duplicate publications (superseded by another publication by the same investigator group, with thesame objective and data)

! Non-English-language articles! Non-systematic reviews, letters, and editorials! Animal and in-vitro studies! Case reports! Studies that did not examine the outcomes of interest

Intervention

! rTMS! Controls do not undergo rTMS but receive optimal conventional medical management

Literature Search

! Cochrane database of systematic reviews! ACP Journal Club! DARE! INAHTA! EMBASE! MEDLINE! Reference section from reviews and extracted articles

Outcomes of Interest

! Adverse effects! Length of time depression-free or relapse-free! Decrease in depressive symptoms! Change in antidepressant usage! Time to adjunctive treatment! Time to when patients go back to work! Time to hospital admissions/time to discharge! Economic analysis data

Results of Literature Review on Effectiveness

Summary of Existing Health Technology Assessments

The Cochrane and INAHTA databases yielded 7 health technology assessments or systematic reviews onrTMS. An overview is shown in Table 2. Each study is described in detail below.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 19

Table 2: Overview of Existing Health Technology Assessments and Systematic Reviewson Repetitive Transcranial Magnetic StimulationPublication

YearAuthor Type Date Literature Search Ended

2004 Martin et al.(3;15)

Cochrane systematic review andmeta-analysis

June 2001; updated March 2002

2003 Aarre et al.(14;36)

Norwegian health technologyassessment

February 2001

2002 Kozel andGeorge (8)

Systematic review and meta-analysis April 2002 (rTMS* versus placeboonly)

2002 Burt et al. (9) Systematic review and meta-analysis Not stated (Article accepted byjournal for publication December5, 2001)

2001 McNamara et al.(37)

Systematic review and meta-analysis January 2000

2001 Holtzheimer etal. (10)

Systematic review and meta-analysis No dates of literature searchreported.No dates of acceptance byjournal for publication.Article published in 2001 autumnissue.

1999 Alberta HeritageFoundation forMedicalResearch (38)

Technology scan No dates of literature searchreported. Date of report was May1999.

* rTMS represents repetitive transcranial magnetic stimulation

Cochrane Systematic Review

Martin et al. (15) conducted a literature search for publications up to June 2001. They also searchedunpublished data and grey literature. They selected RCTs that assessed the therapeutic efficacy andsafety of TMS for depression. They also published an update to their meta-analysis that expanded theliterature search up to March 2002. (3) However, this update only included a meta-analysis of LDLPFCrTMS compared with placebo treatment. It did not include analyses of rTMS variations (e.g., rightprefrontal cortex) or an alternative treatment (e.g., ECT) that the initial Cochrane review provided.

Sixteen trials were included in the initial review; 14 contained data in a suitable form for quantitativeanalysis. Two studies could not be analyzed due to methodological problems. Forty-five studies wereexcluded from the quantitative analysis for the following reasons: they had no or inadequaterandomization, they were narrative reviews, or they were descriptive studies or studies with healthyvolunteers. Two studies had not matured sufficiently for analysis.

Randomization and allocation concealment: None of the studies included in the statistical analysis ofthe initial review provided sufficient detail about accrual.

Blinding of interventions in patients and researchers: Twelve of the 16 studies included in the initialreview were clearly described as double blind or double masked. Martin et al. noted that in theseinterventions it is impossible to blind the professional who applies the technique; therefore, they cannotbe double blinded.

Follow-up: All studies included in the quantitative evaluation described the withdrawals during the study.(39) Only 2 studies (40;41) used intent-to-treat analysis (the method where the last observation is carried

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 20

forward). The rest of the studies, which had withdrawals, did not include these patients in the analyses.Most of the trials had small sample sizes, and some of these trials noted that there were no withdrawals.

Three studies (42-44) had a period of post-treatment follow-up of 2 weeks, and 1 study (41) had a periodof post-treatment follow-up of 1 week between the first and second phase of the crossover design.

Evaluation of depressive symptoms: The score on the Hamilton Depression Rating Scale (HDRS) wasused as the primary outcome variable in all of the studies. The Beck Depression Inventory (BDI) was themost used as a secondary self-administered evaluation.

Methods of evaluating:Most of the studies in the first review reported higher baseline values on theHDRS in patients in the treatment group compared with those in the placebo group, due either to a smallsample size or to inappropriate randomization. An overall analysis (rTMS compared with placebo) of allof the studies was done to determine if there were baseline differences. All 14 studies analyzed showed!"#"$!"$%#&'()*)+,-,$".'/0

213 = 13.37, P=.42). Treated patients had statistically significantly higher

(worse) HDRS scores at baseline than did those in the placebo group. The standardized mean difference(SMD) obtained with a fixed-effect model was 0.30 (95% confidence interval [CI], 0.06–0.54; P=.02).Martin et al. did not comment further on reconciling the difference between a finding of statisticalhomogeneity for the studies and a finding of significant baseline differences in depression scores betweengroups.

Due to this significant difference, and to prevent more regression to the mean (45) in the treatment groupcompared with the placebo group evaluating the change in scores from baseline to the final assessment forthe 2 groups was not recommended. Instead, it was decided to use only the final values of both groups.Therefore, the clinical interpretation of this comparison was the difference in the level of depression inthe patients at the end of the studies between groups. However, this choice of analysis by the authorsraises the question as to the initial appropriateness of even comparing 2 groups when the randomization

in the RCTs may have been flawed.

Regression to the mean is the principle that unusual events are likely to recur. It occurs when anonrandom sample is selected from a population and 2 imperfectly correlated variables are measured,such as 2 consecutive blood pressure measurements. (45) The less correlated the 2 variables, the largerthe effect of regression to the mean. Also, the more extreme the value from the population mean, themore room there is to regress to the mean. Regression to the mean often occurs whenever a group isselected with extreme values for one variable, and another variable is then measured.

The updated meta-analysis by Martin et al. (3) further discussed the rationale for this approach and willalso be discussed in detail in the summary of the paper by Martin et al.

Description of the Scales

Hamilton Depression Rating Scale (HDRS)

! It is generally used in pharmacotherapy studies of people with depression. Various versions exist,each with a different number of items.

! The objective of the scale is to quantify the results of a semistructured interview.! It gives more importance to somatic and behavioural symptoms than to psychological manifestations

of depression.! Low values indicate less depression.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 21

Beck Depression Inventory (BDI)

! It is a self-administered questionnaire. Various versions exist.! It gives more importance to cognitive components than to somatic and behavioural components of

depression.! Low values indicate less depression.

Global Assessment Scale (GAS)

! Scores range from 0 to 100.! It gives a global measure of functioning and symptomatology.! High values indicate better functioning.

Clinical Global Impression Scale (CGI)

! It evaluates the severity of the illness.! It has 3 subscales.! Low values indicate a decrease in the severity of an illness and/or significant recuperation.

Analysis of Efficacy

The first analysis of efficacy compared high-frequency LDLPFC rTMS with placebo TMS. (15)

Outcome: Depressive Symptoms Measured by the Hamilton Depression Rating Scale

! 11 studies (N=197: 109 in the treatment group and 88 in the placebo group).! No statistically significant differences between groups after 1 week of treatment, 1 week of treatment

plus 1 week of post-treatment follow-up, or 2 weeks of treatment plus 2 weeks of post-treatmentfollow-up.

! There was a statistically significant difference between groups after 2 weeks of treatment.

The time variable reported in studies most often was 2 weeks of treatment. After 1 week of treatment(measured in 3 studies), the SMD for rTMS compared with the placebo was 0.02 (95% CI, -0.66–0.70;P=0.9). After 1 week of treatment plus 1 week of post-treatment follow-up (measured in 1 study), theweighted mean difference (WMD) between rTMS and the placebo was 3.80 (95% CI, -4.01–11.61; P=.3).After 2 weeks of treatment (9 studies), the SMD was -0.35 (95% CI, -0.66–0.04; P=.03), in favour ofrTMS. After 2 weeks of post-treatment follow-up (3 studies), there was no longer a statisticallysignificant difference (SMD, -0.33 [95% CI, -0.84–0.17], P=.2).

Outcome: Depressive Symptoms Measured by the Beck Depression Inventory! 7 studies (N= 145: 81 in the treatment group and 64 in the placebo group).! The same subcategories of analysis were performed for the same periods as in the previous analysis.! No statistically significant differences between rTMS and placebo TMS were found for any of the

periods.

After 1 week of treatment (measured in 3 studies), the SMD for rTMS compared with placebo TMS was0.18 (95% CI, -0.47–0.82; P=.6). After 1 week of post-treatment follow-up, the WMD (measured in only1 study) was 6.60 (95% CI, -7.54–20.74; P=.4). The SMD after 2 weeks of treatment (3 studies) was -.24(95% CI, -0.56–0.43; P=.8).

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 22

Outcome: Clinical Global Improvement! 1 study (N= 30: 20 in the treatment group and 10 in the placebo group).! No statistically significant differences were found.

The WMD for rTMS compared with placebo TMS after 2 weeks of treatment was -0.70 (95% CI, -1.77–0.37; P=.2).

The second analysis of efficacy compared low-frequency LDLPFC rTMS with placebo TMS. (15)

Outcome: Depressive Symptoms Measured by the Hamilton Depression Rating Scale! 2 studies (N= 20: 11 in the treatment group and 9 in the placebo group).! There were no statistically significant differences after 1 or 2 weeks of treatment.

After 1 week of treatment (measured in 1 study), the WMD for rTMS compared with placebo was -2.00(95% CI, -13.49–9.49; P=.7). After 2 weeks of treatment (measured in 1 study), the WMD was 2.53(95% CI, -13.53–18.59; P=.8).

The third analysis of efficacy compared low-frequency RDLPFC rTMS with placebo TMS. (15)


! 1 study (N= 67: 35 in the treatment group and 32 in the placebo group).! There was a statistically significant difference in favour of rTMS after 2 weeks of treatment but not

after 1 week.

After 1 week of treatment, the WMD for rTMS compared with placebo TMS was -4.20 (95% CI -8.44–0.04; P=.05). After 2 weeks of treatment, the WMDL was -6.00 (95% CI -10.69–-1.31; P=.01).

Outcome: Clinical global improvement

! There was no statistically significant difference between groups.

After 1 week of treatment, the WMD for rTMS compared with placebo TMS was -0.50 (95% CI, -1.11-0.11; P=.11). After 2 weeks of treatment, the WMD was -0.70 (95% CI, -0.40–0.00; P=.05).

The fourth analysis of efficacy compared high-frequency LDLPFC rTMS with low-frequency LDLPFCrTMS. (15)

Outcome: Depressive Symptoms Measured by the Hamilton Depression Rating Scale! 2 studies (N= 22: 11 in high-frequency group and 11 in low-frequency group).! After 1 or 2 weeks of treatment, no statistically significant difference between the 2 forms of rTMS

was found.

After 1 week of treatment (measured in 1 study), the WMD for the rTMS high vs. low frequency was -.60(95% CI, -10.76–5.56; P=.5). After 2 weeks of treatment (measured in 1 study), the WMD was -0.40(95% CI, –13.84-13.04; P=0.9).

The fifth analysis of efficacy compared vertex motor localization +0.3 tesla rTMS with vertex motorlocalization -0.3 tesla rTMS (15)


! 1 study (N= 10: 5 in +0.3 group and 5 in -0.3 group).! There were no statistically significant differences between groups.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 23

The WMD for the rTMS +0.3 tesla group compared with the rTMS -0.3 tesla group after 1 week oftreatment was 6.40 (95% CI, -1.71–14.51; P=.12).

Outcome: Clinical Global Improvement

! There were no statistically significant differences between groups.

The WMD for the rTMS +0.3 tesla group compared with the rTMS -0.3 tesla group after 1 week oftreatment was 0.40 (95% CI, -1.33–2.13; P=.6).

The sixth analysis of efficacy compared high-frequency LDLPFC rTMS with ECT. (15)


! 1 study (N= 40: 20 in rTMS and 20 in ECT).! The study did 3 comparisons: whole sample, only patients with psychotic symptoms, and only

patients without psychotic symptoms.

Looking at the whole sample, there were no statistically significant differences. After 2 weeks oftreatment, the WMD for rTMS compared with ECT was 1.7 (95% CI, -3.27–6.67; P=.5). There was nostatistically significant difference between the treatment groups after 4 weeks either (WMD, 4.20 [95%CI, -0.74–9.14], P=.10).

No statistically significant differences were found looking at only patients without psychotic symptomseither. After 2 weeks of treatment, the WMD for rTMS compared with ECT was -3.90 (95% CI, -10.90–3.10; P=.3). After 4 weeks of treatment, the WMD was -2.90 (95% CI, -10.26–4.46; P=.4).

Analyzing only patients with psychotic symptoms resulted in a statistically significant difference infavour of ECT. After 2 weeks of treatment, the WMD for rTMS compared with ECT was 7.90 (95% CI,1.98–13.82; P=.009), favouring ECT. After 4 weeks, there was still a significant difference between thetreatment groups favouring ECT (WMD, 12.40 [95% CI, 7.77–17.03], P<.00001).

Outcome: Clinical Global Improvement! Looking at the whole sample, no statistically significant differences were found.

After 2 weeks of treatment, the WMD for rTMS compared with ECT was -2.30 (95% CI, -12.22–7.62;P=.6). After 4 weeks, the WMD was -10.50 (95% CI, -22.85–1.85; P=.10).

No statistically significant differences were found for only patients without psychotic symptoms either.After 2 weeks, the WMD was 8.40 (95% CI, -5.10–21.90; P=.2). After 4 weeks, the WMD was 3.00 (95%CI, -14.61–20.61; P=.7).

Analyzing only patients with psychotic symptoms resulted in a statistically significant difference infavour of ECT. After 2 weeks, the WMD was -14.50 (95% CI, -27.04–1.96; P=.02). After 4 weeks, theWMD was -26.10 (95%CI, -41.12–11.08; P=.0007).

The final analysis of efficacy compared any method of application of rTMS with placebo TMS. (15)

Outcome: Withdrawals During the Study (for any reason)

! 5 studies (N= 184: 99 in the treatment group and 85 in the placebo group).! There were no statistically significant differences between groups.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 24

The relative risk using a fixed-effect model for rTMS (any method of administration) compared withplacebo TMS was 0.81 (95% CI, 0.36–1.83; P=.6).

The authors stated that the limitations in the studies included the following:

! The studies had small sample sizes, and no sample size calculations or justifications were provided.Apart from one study that had 70 patients, the rest had sample sizes of 6 to 40 patients (median, 19).

! The process of randomization was biased. None of the studies discussed the method of concealmentused. Instead, they said only that a study was randomized or described only the generation of theallocation sequence (e.g., with a computer). Therefore, it is impossible to determine if an influence(direct or indirect) existed in the allocation of the patients to different treatment groups. For example,this can happen if the patients who are most likely to respond are put in only the active treatmentgroup. This can influence the results by overestimating a possible treatment effect.

! The allocation to groups was not strictly double blind. In Berman, (40) patients guessed their groupsin 10 of 15 cases. The evaluators deduced the patients’ treatment groups in 12 of 15 cases.

! The HDRS is the most commonly used scale in clinical studies of depression. However, scales basedon semistructured interviews, like the HDRS, are more susceptible to an observation bias than areself-administered questionnaires. All of the studies in the review used the HDRS as a primaryoutcome variable. In the analysis of high-frequency LDLPFC rTMS versus placebo, there was apositive effect of treatment in the HDRS score after 2 weeks of treatment. However, the positiveeffect disappeared using the BDI (although the BDI comparison used fewer studies, because sometrials lacked numerical data). The only study that found an effect in favour of rTMS using the HDRS(40) showed no difference between groups in the BDI scores.

! Diversity of pathology (definition of treatment resistance, chronicity).! The techniques to treat patients were diverse (e.g., high-frequency, low-frequency, location of coil,

motor threshold).! The observed placebo effect is not well understood. Patients who received placebo rTMS may have

received a small dose of magnetic energy that may have altered their depression.

Reviewers’ Conclusions:Martin et al. concluded, “There is no strong evidence for a possible efficacy ofTMS for the treatment of depression, although these results do not exclude the possibility of benefit.” (15)

Currently in the United Kingdom, the NHS Research and Development Health Technology AssessmentProgramme is sponsoring a multicentre randomized clinical trial to assess the effectiveness and cost-effectiveness of rTMS compared with ECT for severe depression. (46) The project started in August2001, and its results are expected to be published mid 2005.

The aims of this study are to carry out a multicentre RCT with 6 months follow-up for rTMS comparedwith ECT in patients with severe depression. Ninety patients will be entered into each arm of the trial,which is sufficient to obtain a 95% CI to demonstrate equivalence or a subtle difference between rTMSand ECT. The objectives of the RCT are as follows:

! To determine if rTMS is as effective as ECT! To determine if rTMS is associated with fewer adverse effects than ECT! To identify patient characteristics indicative of a beneficial response to rTMS! To ascertain if patients prefer rTMS or ECT

The objectives of the cost-effectiveness analysis of rTMS compared with ECT are as follows:

! To calculate the short- and longer-term costs of treatment of rTMS and ECT

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 25

! To establish if there are economic as well as therapeutic advantages of rTMS compared with ECT inthe immediate and long term

Martin et al. Updated Literature Search

In another publication, Martin et al. (3) reported an updated literature search extending up to March 2002.Included were RCTs that compared rTMS at any frequency and at any localization with a placebointervention. Patients were of any age and sex and had a diagnosis of depression (depressive disorders orbipolar disorders in depressed phase), with or without psychotic symptoms, according either to theDiagnostic and Statistical Manual of Mental Disorders IV (DSM-IV; American Psychiatric Association,1994) or to the ICD-10 (World Health Organization, 1993).

Eighty-five references were identified, of which 48 were excluded for the following reasons:

! 17 trials had no control group.! 7 trial reports whose outcomes efficacy outcomes had been published elsewhere.! 9 studies used healthy volunteers.! 1 had no report of any randomization process.! 1 was a descriptive study.! 2 studied outcomes other than depression.! 2 gave rTMS after a previous intervention of sleep deprivation.! 16 studies were still in progress: either the data were incomplete or the authors were awaiting data.

Five studies were excluded from the identified trials because there was either no placebo comparisongroup or because although a placebo group was included with 2 randomly allocated active-treatmentgroups, the control group itself had not been generated by a randomization process. The detailed analysisof the 5 studies was included as part of the larger Cochrane review previously published by Martin et al.

Among the 16 RCTs there was clinical heterogeneity with respect to 4 variables:

! Localization of rTMS application (LDLPFC, RPFC, vertex, or multiple sites)! Frequency of rTMS (high or low)! Duration of treatment (10 consecutive working days [2 weeks] or 5 consecutive working days [1

week])! Number of interventions per day (1 or more)

The process of inclusion of studies is presented in Figure 1. Two studies (47;48) were awaiting evaluationof design data and methodological quality to be included; additional quantitative information was neededfor these studies to be analyzed. (3)

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 26

Some studies of 2 weeks duration measured outcomes at both 1 and 2 weeks.†HDRS represents Hamilton Depression Rating Scale; BDI, Beck Depression Inventory; ECT, electroconvulsivetherapy, rTMS, repetitive transcranial magnetic stimulation.

*Used with permission from the Royal College of Psychiatrists; Martin JL, Barbanoj MJ, Schlaepfer TE, Thompson E, Perez V.

Repetitive transcranial magnetic stimulation for the treatment of depression: systematic review and meta-analysis. Br J Psychiatry

2003; 182:480-491 (3)

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 27

Fourteen studies met the inclusion criteria. (3) The majority of the studies (13/14) compared LDLPFCwith a group receiving a placebo, but 1 study compared it with low-frequency RPFC. The duration of thetreatment was 2 weeks in 9 of the LDLPFC studies and 1 week in the remaining 3 studies. A summary ofthe studies is presented in Table 3.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 28

Table 3: Summary of Studies Comparing the Effectiveness of rTMS With a Placebo*

*Used with permission from the Royal College of Psychiatrists; Martin JL, Barbanoj MJ, Schlaepfer TE, Thompson E, Perez V.

Repetitive transcranial magnetic stimulation for the treatment of depression: systematic review and meta-analysis. Br J

Psychiatry 2003; 182:480-491 (3)

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 29

Only 3 studies reported that patients were free of antipsychotic medication for 1 week before the studyand during the study itself. In 7 of the 14 studies, the patients were described as “medication resistant”(i.e., having failed at least 1 trial of pharmacotherapy during the current depressive episode). In somestudies, pharmacotherapy was continued, whereas in others it was not.

Most studies excluded patients at high risk of suicide. Some studies recruited only outpatients. Othersrecruited only inpatients. Some recruited both; others did not specify the pattern of recruitment (Table 4).

Table 4: Patient Medication Regimens During the Studies.

Used with permission from the Royal College of Psychiatrists; Martin JL, Barbanoj MJ, Schlaepfer TE, Thompson E, Perez V.


Psychiatry 2003; 182:480-491

The updated results from the systematic review by Martin et al. (3) are similar to the initial results thatwere reported in the Cochrane review. (49)

Hamilton Depression Rating Scale (LDLPFC high frequency vs. placebo)

Subgroup analyses were done for duration of treatment (1 or 2 weeks) and for length of follow-up (1 or 2weeks). (3)

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 30

After 2 weeks of treatment (measured in 9 studies), the SMD for rTMS compared with placebo treatmentwas -0.35 (95% CI, -0.66–0.04; P=.03), showing a difference in favour of rTMS. For studies thatreported data after 1 week of treatment or only gave treatment for 1 week (5 studies), the SMD for rTMScompared with placebo treatment was not statistically significant (SMD, -0.18 [95% CI, -0.64–0.27];P=.4).

After 1 week of post-treatment follow-up (measured in 2 studies), the SMD was 0.08 (95% CI, -0.64–0.81); P=.8). After 2 weeks of post-treatment follow-up (3 studies), the SMD was not statisticallysignificant (SMD, -0.33 [95% CI, -0.84–0.17]; P=.2).

Results for the HDRS scores are presented in Table 5.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 31

Table 5: Effect Size (Remission of Symptoms) for the Fixed-effect Model of rTMSCompared With Placebo rTMS for Depression on the HDRS Scale*

*Subgroup analyses pooled by time; rTMS represents repetitive transcranial magnetic stimulation; HDRS,Hamilton Depression Rating Scale.Used with permission from the Royal College of Psychiatrists; Martin JL, Barbanoj MJ, Schlaepfer TE, Thompson E, Perez V.


Psychiatry 2003; 182:480-491 (3)

Beck Depression Inventory (LDLPFC high frequency vs. placebo)

There was no difference between rTMS and placebo for any of the times using the BDI. After 1 week oftreatment (measured in 3 studies), the SMD for the rTMS compared with placebo treatment was 0.18

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 32

(95% CI, -0.47–0.82; P=.6). After 2 weeks of treatment (6 studies), the SMD was -0.24 (95% CI, -0.58–0.11; P=.18). The SMD after 2 weeks of post-treatment follow-up (3 studies) was -0.06 (95% CI, -0.56–0.43; P=.8). Results for the BDI are presented in Table 6.

Table 6: Effect Size (Remission of Symptoms) in the Fixed-effect Model of rTMS Compared With

Placebo rTMS for Depression on the Beck Depression Inventory*

*Subroup analyses pooled by time; rTMS represents repetitive transcranial magnetic stimulation.Used with permission from the Royal College of Psychiatrists; Martin JL, Barbanoj MJ, Schlaepfer TE, Thompson E, Perez V.


Psychiatry 2003; 182:480-491 (3)

Acceptability of treatment

Four studies reported withdrawals of patients during intervention, with a total sample size of 114 patients(63 in the treatment group and 51 in the placebo group). The relative risk using a fixed-effect model for

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 33

rTMS compared with placebo rTMS for all patients was not significant (SMD, 0.88 [95% CI, 0.37–2.13];P=.8).

Methodological Considerations

All of the studies had serious major methodological weaknesses including the following:

Small sample size (median, 19)

! Uncontrolled variables that may influence outcomes may not be sufficiently evenly distributedbetween treatment and control groups.

! In all except 3 of the studies, all or a proportion of the patients (in the treatment and control arms)were taking some form of psychotropic medication. This may have affected the results.

In some cases, the authors stated that patients were “medication resistant,” but the definition of resistancewas unclear; therefore, the potential for concurrent medication to interfere with the performance of therTMS procedure cannot be ruled out.

! None of the included studies provided information on the method of allocation concealment used.(e.g., the patients who are most likely to respond could have been included only in the activetreatment arm).

Rather than using the term “double blind,” it is more accurate to consider the trials as having been singleblind with an evaluation by external blinded assessors.

! There is the potential for the patients to guess their group allocation through nonverbalcommunication with the administrator of the intervention.

! Wasserman and Lisanby (7) reported that, depending on the way a placebo is delivered, the physicalsensation experienced can differ for placebo and active treatment, thereby effectively alerting thepatient to the treatment being given.

Measurement of treatment outcomes using scales or inventories.

! The most common scale, the HDRS, is based on a semistructured interview. Some authors (2) havereported that rating scales based on semistructured interviews are more susceptible to observation biasthan are self-administered questionnaires such as the BDI. Martin et al. (3) argued that the lack ofconsistency in effect as determined by the 2 scales (a positive score after 2 weeks of treatment asmeasured by the HDRS and a negative scored on the BDI) makes definitive conclusions about thenature of the change in mood of the patients impossible.

! Martin and colleagues suggested that, because of difficulties interpreting results from psychometricscales, (4) and the subjective or unstable character of MDD, the use of other, more objective, outcomemeasures should be taken into account in the assessment of rTMS for depression. These includereadmission to hospital, time to hospital discharge, time to adjunctive treatment, and time off work.

Complexity of possible combinations for administering rTMS makes comparison of like versus likedifficult.

! Martin et al. (3) categorized the 3 main variations in administration methods: localization on the skull,frequency of treatment, and duration of treatment. In most of the included studies, rTMS was appliedto the LDLPFC, but Wasserman and Lisanby (7) have stated that the method for precisely targetingthe stimulation in this area is unreliable.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 34

! Moreover, it is unknown if the LDLPFC is the optimal localization for treatment.! Differences that Martin and colleagues did not categorize include the shape of the coil, the number of

trains per session, and the duration of each train.

Data Analysis Considerations

Martin et al. (3) noted that in 8 of the 12 studies in the updated meta-analysis for the HDRS, and in 6 ofthe 7 studies in the updated meta-analysis for the BDI, the baseline mean values for the severity ofdepression were higher in the treatment group than in the placebo group. They said, “Although thesedifferences were not statistically significant at the level of each individual study, they would haveintroduced a potential bias within the meta-analysis of pooled data by accentuating the tendency forregression to the mean of the more extreme values.” If the patients who are most likely to respond (i.e.,the sickest patients) are only in the active treatment arm, it can influence the final results of the studies byoverestimating a possible effect of treatment.

Martin et al. acknowledged their study was limited because individual patient data were not availablefrom all the studies, and an appropriate adjustment according to baseline severity was not possible.However, to reduce potential bias caused by these differences in baseline values, Martin et al. onlycompared final values on depression severity between the active and control groups. The authorsdefended their analysis by stating that they used the means and standard deviations because, “Weconsidered that owing to probable baseline imbalance between the studies, these estimates reflect a moreprecise effect size than a dichotomous measure such as the rate of improvement…derived from thecontinuous data of the rating scales.” However, this choice of analysis by the authors raises the questionas to the initial appropriateness of even comparing 2 groups when the randomization process may have

been flawed.

Regression to the mean occurs whenever a nonrandom sample is selected from a population and 2imperfectly correlated variables are measured, such as 2 consecutive blood pressure measurements. (45)The less correlated the variables, the larger the effect of regression to the mean. Also, the more extremethe value from the population mean, the more room there is to regress to the mean. Regression to themean occurs whenever a group is selected with extreme values for one variable and another variable isthen measured. Given the limitations of the data to date, it would be useful to conduct an RCT and dosample size calculations with patient groups that are appropriately randomized and comparable at

baseline on the severity of their depression.

Discussion of Results

! Martin et al.(3) stated that the results to date are not very encouraging. However, they also suggestedthat their results should not be a reason to abandon rTMS as a treatment for depression altogether.

! The number of patients included in studies of the efficacy of rTMS falls short of the number ofpatients registered in trials for new drug treatments. In addition, longer-term results are required forpatients receiving rTMS.

! Technical details such as where to stimulate, at what frequency, the total number of stimuli, and theduration of the treatment have yet to be resolved.

! There is a need for “thorough randomized controlled multicentre studies involving large numbers ofpatients.” (3)

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 35

Clinical Implications

! The findings from the systematic review and meta-analysis provide insufficient evidence to suggestthat rTMS is effective in the treatment of depression.

! There were several confounding factors in the included studies that should be kept in mind beforeconsidering rTMS for clinical use.

! The rTMS technique needs more high-quality trials to show its effectiveness for therapeutic use.

Limitations

! There was a lack of pragmatic variables in the studies, such as time to further treatment, time offwork, readmission to hospital, or hospital discharge.

! Individual patient data from all the studies were not available; therefore, an appropriate adjustmentaccording to baseline severity was not possible.

! There was poor follow-up evaluation in the studies.

Norway – Aarre et al.

Aarre et al. (14;36) systematically reviewed all published evidence on the treatment of depression withrTMS. Inclusion criteria were RCTs that compared rTMS with placebo rTMS or with ECT. Case reportsand uncontrolled studies were excluded. This report by Aarre et al. (14) is an abbreviated version of alengthy report published in Norwegian by the Norwegian Centre for Health Technology Assessment. (36)

Results: Of 225 reports identified in a literature search up to the end of February 2001, 12 studies wereconsidered to be of sufficient scientific quality to include in the review. Aarre and colleagues said that aformal meta-analysis was not feasible, because the studies varied too much in design, in the way thatrTMS was administered, and in patient characteristics.

Efficacy in Depression: Of the 12 studies included, the results were inconsistent. Most studies showedmodest efficacy, with patients somewhat improved after receiving rTMS, although still in need of furthertreatment. Some studies found no clinically significant effects of rTMS, but 2 studies found robustefficacy in patients with severe depression. Aarre et al. stated that the inconsistent findings may be due todifferences in study design, the kind of rTMS administered, and patient characteristics.

They also stated that no study has yet shown that an effect for TMS persists beyond 2 weeks followingtreatment cessation, and that few studies have long-term follow-up data.

Furthermore, they noted that the quality of the study designs was poor. The 12 included studies had smallsamples, and highly variable inclusion criteria and study designs. The patients were often insufficientlycharacterized as to previous history, diagnosis, treatment history, and treatment setting. In addition, manystudies stated that the patients had treatment-resistant depression without outlining any clear criteria forthis designation. Without this information, Aarre et al. suggested that the interpretation of the results isdifficult and that the generalizability is questionable.

Stimulus site, Frequency, and Intensity:Most trials studied the effect of stimulating the LDLPFC.Stimulus frequency varied among studies: 20, 10, 1, and 0.1 Hz were used. Stimulus intensity alsovaried, from 110% to 80% of the motor threshold. Aarre et al. could draw no conclusions about theoptimal stimulus site, frequency, or intensity.

Placebo Condition and Blinding: In most of the reviewed studies, placebo rTMS was administered byplacing the coil tangential or at an angle of 45 degrees to the scalp. This positioning does not elicit the

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 36

twitching in scalp muscles that is often seen with real rTMS. This difference in effect may have allowedsome of the patients to guess which treatment they had received. This problem was addressed in Bermanet al. (40) In that study, 67% of patients correctly identified the treatment they had received. As well, justgenerally, some placebo conditions may have active properties. (9)

Masking the treatment is a concern in studies using a crossover design. Bohlan et al. (50) have shownthat patients are able to discriminate between active and placebo rTMS.

Blinding is very difficult, if not impossible, to achieve in a rTMS study when ECT is the comparator. (14)This is unavoidable, because ethical issues would arise in trying to approve a study that anesthetizespatients unnecessarily just to achieve appropriate blinding for scientific purposes.

Use of Active Comparators: Aarre et al. (14) noted that it might be premature to compare rTMS with anactive comparator. They argued that when there is a lack of consistency as to the efficacy of the treatment,RCTs with active comparators should not be done unless sample sizes are large enough to make type IIerrors unlikely. In the studies with the small sample sizes that were reviewed, it is highly probable thattype II errors were made. If so, this would have led to the conclusion that there is no difference betweentreatments, where indeed such differences may exist. Therefore, trials with active comparators wouldexpose more patients to possibly inferior treatments than would be the case with placebo-controlled trials.

Aarre and colleagues concluded that rTMS cannot be recommended as a standard treatment fordepression: “More, larger and more carefully designed studies are needed to demonstrate convincingly aclinically relevant effect of rTMS.”

Meta-Analysis of LDLPFC rTMS versus placebo

Kozel and George (8) did a meta-analysis to assess the use of rTMS over the LDLPFC to treat depression.The authors analyzed rTMS over the LDLPFC because most of the studies in the literature have treatedthe LDLPFC part of the brain. The literature was searched for RCTs up to April 2002.

To reduce a possible confounding order effect of prior knowledge of TMS or placebo rTMS affecting theeffectiveness of the masking, only data for patients who said they had never received rTMS or placeboTMS were used. For studies that used crossover designs, only data from the initial randomized groupwere used. The outcome variable for all studies was the change in scores on the HDRS. A positive effectwas defined as an improvement in depressive symptoms during the trial (i.e., baseline HDRS score minusthe post-rTMS/placebo HDRS score = positive value). Effect sizes were calculated (using Hedges’ d).

Twelve studies met the inclusion criteria. (See Table 7.) The details of these trials follow.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 37

Table 7: Double-Blind Placebo-Controlled Treatment Trials of LDLPFC rTMS*

*LDLPFC represents left dorsolateral prefrontal cortex; rTMS, repetitive transcranial stimulation. From:Kozel and George (8)

Kozel and George (8) calculated that the average change in mean HDRS scores from before rTMS to afterrTMS was 7.20 (SE, 0.96) for the active group and 3.58 (SE, 0.89) for the control group. Because themean change in HDRS scores includes responders and nonresponders, the group change for those whoreceived active rTMS was relatively small but significantly greater (t 3.89, P=.0025) than for those whoreceived a placebo. The test for heterogeneity was not significant (Qtotal 10.65, 0

211 0.47). Therefore,

Kozel and George used a fixed-effects model to calculate the summary statistic.

The summary analysis of all 12 studies (n=230) revealed a cumulative effect size of 0.53 (95% CI, 0.24–0.82). The summary analysis is presented in Figure 2.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 38

Figure 2: Forrest plot of Hedges’ d effect size and 95% confidence interval for LDLPRCrTMS treatment of depression. The horizontal axis indicates Hedges’ d effect size.*

*LDLPFC represents left dorsolateral prefrontal cortex; rTMS, repetitive transcranial stimulation. From:Kozel and George (8)

A funnel plot evaluation was used to analyze the potential impact of unpublished studies. In this type ofevaluation, if the plot does not have a symmetric funnel shape, it indicates there are likely to beunpublished studies that may provide nonsignificant results. According to the authors, the funnel plotshown in Figure 3 indicated that a publication bias might have been possible.

Figure 3: A Funnel Plot Evaluation To Examine the Effect of Unpublished Studies*

*The plot indicates that there are likely unpublished studies that found nonsignificant results since the plot does nothave a symmetric funnel shape tapering down as the variance (horizontal axis) gets smaller. Smaller variancesindicate larger sample sizes. The studies with larger sample sizes would have less variability in results versus thestudies with smaller sample sizes. One would expect the graphed points to have a “funnel” shape if all studies usingrTMS including those showing no effect had been published. From Kozel and George. (8)

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 39

Orwin’s formula was used to calculate the number of studies with findings of nonsignificance that wouldbe required to shift the result of the meta-analysis from significant to. Kozel and George estimated thatabout 20 unpublished studies with no significant findings would be required to render the overallsummary statistic nonsignificant.

Kozel and George concluded that the following are still unknown about rTMS treatment for depression:

! The duration of improvement after acute treatment! Whether maintenance rTMS could be used to prolong benefits! Relationship between pharmacotherapy use and rTMS

The limitations of Kozel and George’s meta-analysis include the following:

! All of the limitations applicable to the meta-analysis by Martin et al. (3)! Varying TMS parameters were used. These include waveform, coil type, size and orientation,

stimulus intensity, pulse frequency, train duration, inter-train interval, number of trains, and numberof treatment sessions. According to Kammer et al. (51), there was variability in rTMS deliveryaccording to device type (Dantec Magpro, Magstim 200, and Magstim Rapid).

! 2 studies were not included in the analysis due to inability to determine required data from thepublication or response from the first author.

! The results may be statistically significant, but they are not necessarily clinically significant.(8) Themean change in HDRS scores for patients who received active rTMS was small but significantlydifferent from that for patients who received a placebo. Conventionally, many studies consider asuccessful clinical response to be a 50% decrease in the HDRS score.

Meta-analysis of rTMS Compared With Various Other Interventions

Burt et al. (9) did a meta-analysis to assess the treatment effect of rTMS for 3 categories of studies ofpatients with depression: open and uncontrolled trials; placebo or otherwise controlled trials; andcomparisons of rTMS and ECT. For each study, the percentage change in HDRS scores were reported.One study, by Pridmore et al., (52) reported scores from the Montgomery-Asberg Depression RatingScale (MADRS).

Burt et al. did not report any details of the literature search they did for the meta-analysis. Weightedmean effect sizes combining studies were reported for both Cohen’s d and Hedges’ adjusted g.Weighting was based on a function of a study’s sample size and the precision of the effect size estimate.The Hedges’ g statistic provides a more conservative estimate of the combined effect size.

Open and Uncontrolled Trials

The first two tables in Appendix 3 summarize the open and uncontrolled studies of rTMS in the treatmentof major depression.

Across the 9 studies that reported changes in depression scores, the combined weighted effect size(Cohen’s d) was statistically significant (d=1.37). There was no evidence of heterogeneity in the effectsize for either Cohen’s d (Q8=6.69, P=.57) or Hedges’ g (Q8=5.41, P=.71). (9) (See Figure 4)

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 40

Figure 4: Effect Size (d) and 95% Confidence Interval for Open and Uncontrolled Studiesof TMS and rTMS in the Treatment of Depression*

*rTMS represents repetitive transcranial stimulation. The size of the boxes is proportional to thesample size. The overall combined effect size is indicated by a diamond.

Burt T, Lisanby SH, Sackeim HA. Neuropsychiatric applications of transcranial magnetic stimulation: a meta analysis.

International Journal of Neuropsychopharmacology 2002; 5(1):73-103; Subject to the copyright notice provided by Cambridge

University Press, Reprinted with the permission of Cambridge University Press and the author (9)

The patient sample reported by Epstein et al. (1998) overlapped with the study by Figiel et al. (1998).When the authors excluded the study by Epstein et al., the effect size (Cohen’s d) for the remaining 8studies increased to 1.45.(9)

Despite the size of the effect, the degree of therapeutic change across these studies was relatively modest.The unweighted mean reduction in the HDRS or MADRS scores was 37.03% (standard deviation [SD],29.23). Conventionally, as noted earlier in this report, the outcome of interest in trials is a 50% reductionof the HDRS score. Therefore, relatively few patients in these studies would meet the standard criteriafor response or remission. The findings from the open and uncontrolled studies suggested that slow or fastrTMS may have antidepressant properties, but the clinical significance of this effect is uncertain.

Placebo and Other Controlled Trials

The third and fourth tables in Appendix 3 summarize the placebo- or otherwise-controlled studies of TMSand rTMS to treat depression. Several studies included a single placebo condition and 2 activeTMS/rTMS conditions. The authors included each of these comparisons as individual observations.Therefore, because patients who received placebos were compared to each active condition, the totalnumber of patients is artificially large and duplicates patients. Similarly, in studies that used a crossoverdesign, each phase of the study is presented as a separate comparison. Two studies did not involve aplacebo comparison. Conca et al. (55) compared a group assigned to TMS plus medication with a grouptreated with medication only. Kimbrell et al. (57) compared high-frequency LDLPFC rTMS (20 Hz) withlow-frequency LDLPFC rTMS (1Hz). Because this latter study had 2 active treatments, its inclusion inthe meta-analysis may be questionable. However, Burt et al. included it because the predominanthypothesis in the field was that high-frequency LDLPFC rTMS would be more effective.

The combined effect size (Cohen’s d) for the 23 comparisons was 0.67, which indicates a moderate tolarge effect. As shown in Figure 5 below, Cohen’s d also indicated that there was significantheterogeneity in the effect size (Q22=47.08, P=.001); however, the detection of heterogeneity wasmarginal with the more conservative Hedges’ g (Q22=33.21, P=.06).

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 41

Figure 5: Effect Size (d) and 95% Confidence Interval for Randomized Controlled Trials of TMS andrTMS in the Treatment of Depression*

*rTMS represents repetitive transcranial stimulation. The size of the boxes is proportional to the samplesize. The overall combined effect size is indicated by a diamond. Figures within brackets following thestudy’s authors refer to specific comparisons within a study.

Burt T, Lisanby SH, Sackeim HA. Neuropsychiatric applications of transcranial magnetic stimulation: a meta analysis.

International Journal of Neuropsychopharmacology 2002; 5(1):73-103; Subject to the copyright notice provided by Cambridge

University Press, Reprinted with the permission of Cambridge University Press and the author (9)

Stikhina et al. (1999) reported an especially large effect size. In this study, rTMS was administered at anintensity that is unlikely to have biological effects (0.015 tesla) to patients who were characterized ashaving “neurotic depression.” Removing this study did not influence the overall results.

Kimbrell et al. (57) found that low-frequency rTMS (1 Hz) over the LDLPFC had a superior outcome tohigh-frequency rTMS (20 Hz) over the same location. If this study was removed, the heterogeneity incombined effect size would still be significant for Cohen’s d (Q21=37.96, P=.01) but not for Hedges’ g(Q21=27.45, P=.16).

Burt et al. also examined if the effect sizes differed in studies using slow rTMS (<1 Hz) or fast rTMS(>1Hz). Five comparisons involved slow rTMS, and 18 comparisons involved fast rTMS. The pointestimate for Hedges’ g was higher for slow rTMS (g=0.68, SE=0.17, z=3.93, P=.0001) than for fast rTMS(g=0.58, SE=0.13, z=4.37, P<.0001). These analyses suggest that higher-frequency stimulation dos notnecessarily enhance the antidepressant properties of TMS.

Moreover, the magnitude of the effect was of doubtful clinical significance. The authors re-examined thetherapeutic effect after excluding 3 questionable comparisons that may have biased these results: thePascual-Leone et al. (1996b) use of rTMS over the RDLPFC, the Kimbrell et al. (1999) (57) comparisonsof 20 Hz and 1 Hz rTMS/TMS over the LDLPFC, and the Stikhina et al. (1999) use of 0.015 teslastimulation over the LDLPFC. The mean unweighted percentage improvement in the HDRS scores in theactive conditions of the remaining studies was 28.94% (SD, 23.19). The mean percentage improvementwith placebo was 6.63% (SD, 25.56). Again, the therapeutic change was modest with rTMS;

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 42

furthermore, relatively few patients met the standard criteria for successful response (50% reduction inHDRS score) or remission (final HDRS <8). (9)

Burt et al. concluded that the modest therapeutic effects of rTMS in major depression may suggest that itsprimary role might be as an add-on or augmentation strategy. Most of the studies in Tables 3 and 4 ofAppendix 3) limited rTMS administration to either 5 or 10 sessions, corresponding to approximately 1 or2 weeks of treatment. Antidepressant medications typically have a delayed onset of action. Burt et al.suggested that a role for either slow or fast rTMS might be to provide some symptom relief while patientsawait the full impact of antidepressant medications. They classified the 23 comparisons according towhether or not the sample was medication free. If most of the patients were not receiving antidepressantmedications, the comparison was classified as medication free. For 8 comparisons of medication-freepatients, Hedges’ g point estimate was 0.71 (SE= 0.12, z=5.92, P<.0001). For 15 comparisons of patientsreceiving medication, Hedges’ g point estimate was 0.60 (SE=0.20, z=3.03, P=.003). Based on theseresults, it did not appear that concomitant pharmacotherapy either enhanced or detracted from thetherapeutic effects of rTMS.

Burt et al. stated that the issue of medication resistance deserves greater attention. The studies to datehave recruited patients reported to have medication-resistant depression, or they have comprised mostlypatients with medication-resistant depression. Medication resistance is a negative predictor of response toECT. Burt et al.suggested that whether slow or fast rTMS has greater clinical potential when administeredto patients earlier in the course of antidepressant treatment still needs to be determined. Furthermore, therelationship between degree and specific forms of medication resistance and rTMS response need to bedetermined. The authors supported their claim by stating that there is evidence that failure to respond toadequate treatment with a selective serotonin reuptake inhibitor has little predictive value for ECTresponse. Conversely, failure to respond to adequate treatment with a tricyclic antidepressant predicts alower response probability.

Comparisons With Electroconvulsive Therapy

The fifth and sixth tables of Appendix 3 summarize the 3 studies that randomized patients to treatmentwith either rTMS or ECT. According to Burt et al. (9), a meta-analysis of the 3 studies (n=112) yielded acombined Cohen’s d of 0.21 favouring ECT. No plot of the combined effect size or 95% CI was reportedby the authors. There was no significant heterogeneity in effect size (i.e., no data were reported).

The mean improvement in HDRS scores in rTMS conditions was 47.13%, about double the degree oftherapeutic improvement observed in the 23 comparisons of the controlled studies in Tables 3 and 4.However, the reasons for this greater therapeutic effect (which was also of greater clinical significance)are unknown. Burt and colleagues considered 2 possibilities:

! The studies provided longer courses of rTMS (20 sessions in the studies by Grunhaus et al.(unpublished data) and the number of treatments based on degree of clinical progression in the studyby Pridmore et al. (52) Therefore, it is possible that extended treatment with rTMS may have greaterantidepressant effects.

! The samples in these studies were selected for receiving ECT. Typically, patients selected for ECTare unique in the severity of their depressive symptoms and the presentation of endogenous ormelancholic features. They also have a high rate of psychotic depression. A more favourable rTMSresponse may have existed in these patients with severe depression.

Additionally, the mean improvement in HDRS scores with ECT was only 54.47%, which is relatively lowfor this form of treatment. Previous studies on high-dosage ECT reported a 69% to 73% improvement inHDRS scores immediately after treatment. When patients with psychotic depression were excluded, these

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 43

values were 75.66% (SD, 29.68) for high-dose bilateral ECT and 72.92% (SD, 25.37) for high-dose rightunilateral ECT. Therefore, Burt et al. suggested that the degree of improvement observed with ECT in therTMS/ECT comparisons was suboptimal. The reason for this is unknown, but Burt and colleaguessuggested an underestimation of the therapeutic effects of ECT relative to prolonged courses of rTMS.

TMS in the treatment of depression: age

Kozel et al.(53) suggested that prefrontal atrophy advances at a greater rate with aging, which may resultin the underdosing of magnetic stimulation to older patients.

Limitations to the meta-analysis of Burt et al. (9) included the following:

! No report of the details of the literature search they did for the meta-analysis! All of the limitations previously mentioned in Martin et al. (3)! Small size of trials; no sample size calculation or justification! No discussion of the baseline depression values among the study groups! No discussion of randomization bias

Meta-analysis of rTMS compared to placebo, McNamara et al.

McNamara et al. (37) conducted a systematic review and literature search up to January 2000. The aim ofthe study was to evaluate the evidence for the effectiveness of rTMS in mood disorders. Placebo-controlled RCTs were included. Explicit exclusion criteria were not reported.

Results

Sixteen published clinical trials of rTMS for depression were identified. Eight studies were excludedbecause they did not have a randomized control group. One study was excluded because people in thecontrol group were treated with ECT. (54) Another study was excluded because there was no placeboTMS treatment included as part of the trial protocol. (55) Yet another trial, which had 18 patients andfailed to show any significant benefit of rTMS, was excluded because the “individual responses” ofpatients in the TMS and control groups were not available. (56)

Therefore, 5 studies were included in the meta-analysis. The standardized placebo treatment wasapplication of the TMS coil at an ineffective angle of 45 or 90 degrees on the scalp. All of the trialsincluded only patients who met DSM criteria for a major depressive episode. In 4 of the 5 studies, thepatients remained on antidepressant medication. In the remaining study, medication had been withdrawnfor at least 1 week prior to commencing the trial.

The authors reported that “the overall chi squared test of association was 13.3 (df=1), implying astatistically significant benefit of rTMS (P<.001).” There was no significant heterogeneity in the studies(Q4 = 5.3, P>.1). The difference between the undefined “rate of improvement” in the treated group andthat in the control group was 43% (95% CI, 25%–61%). The estimated number-needed-to-treat was 2.3(95% CI, 1.6–4.0). McNamara et al. did not further discuss the number needed to treat. The duration ofthe therapeutic response was not defined in any of these studies.

Adverse Effects

There were no withdrawals from treatment due to adverse effects. No seizures were reported. In all thestudies, patients reported getting transient headaches after the TMS sessions. In all cases, it was reported

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 44

that the headache resolved spontaneously or responded to treatment with analgesics. The only otheradverse effect recorded was local scalp discomfort at the site of the treatment during the session.

McNamara et al. stated that further large trials will be needed if rTMS is to be considered as an alternativeto ECT in treating selected patients with depression. Specifically, they noted that the following questionswill need to be answered in future trials:

! Is rTMS as effective as ECT in depression?! What is the most effective treatment regimen for rTMS?! Are there any subgroups of patients who do particularly well with rTMS?

Limitations to the meta-analysis by McNamara et al. included the following:

! Some patients may not have been blinded by the placebo condition (orientation of coil to scalp).! Duration of antidepressant effect was not defined in any of the studies.! Small size of trials; lack of sample size calculation or justification.! No discussion of the differences between the studies.! No discussion of the baseline depression values among the groups.! No discussion of randomization bias.

Meta-analysis of rTMS compared with placebo, Holtzheimer et al.

Holtzheimer et al. (10) conducted a meta-analysis of rTMS in the treatment of major depression. Thescope of the study was limited to placebo-controlled studies of rTMS applied to the prefrontal cortex inthe treatment of major depression. A literature search was conducted, but no cut-off dates were reported.Inclusion criteria consisted of the following:

! Placebo-controlled study design (crossover or parallel groups); studies that used another treatment fordepression as a control (such as medication alone or ECT) were excluded

! Patients with depression (MDD or bipolar disorder, depressed)! Reported means and standard deviations for HDRS scores before and after treatment; the 17-, 21-, or

25-item HDRS was accepted! Prefrontal cortical stimulation (left or right) as the treatment condition! No overlap in patient population with another included study

Thirteen placebo-controlled studies were initially identified. Of these, one did not provide theinformation necessary to determine its adequacy for inclusion or to calculate an effect size. Therefore, 12studies were included in the meta-analysis. This allowed for the calculation of 16 individual SMD effectsizes. Initial results for the overall weighted mean effect size failed homogeneity testing, so a random-effects model was applied.

The overall weighted mean effect size, based on the raw decrease in HDRS scores in the 12 studies (16effect sizes) was 0.81 (95% CI, 0.42–1.20, P<.001). The weighted mean effect size for those studiesusing LDLPFC stimulation (11 studies, 14 effect sizes) was 0.89 (95% CI, 0.44–1.35, P<.001). Theweighted mean effect size for those studies using LDLPFC stimulation in a parallel-groups design (7studies, 9 effect sizes) was 0.88 (95% CI, 0.22–1.54, P<.01). In the last analysis, it was noted that 1 studywas a distinct outlier. (40) The weighted mean effect size excluding this study (6 studies, 8 effect sizes)was 0.63 (95% CI, 0.15–1.11, P<.01).

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 45

Eleven of the 12 studies reported the number of responders, which was defined as a more than 50%decrease in HDRS scores. Overall, 25 (13.7%) of the 183 patients treated with rTMS were classified asresponders compared with 10 (7.9%) of 127 patients given the placebo stimulation. These data appearedto have been heavily influenced by one study in which a relatively large proportion of patients in both ofthe conditions responded. (5) When this study was excluded, 7 (4.7%) of 148 patients treated with rTMSand 2 (2.1%) of 95 patients given placebo stimulation were classified as responders.

Four of the 12 studies included in this analysis commented on the duration of antidepressant effects ofrTMS when present. Pascual-Leone et al. (47) reported that the antidepressant effects seen with LDLPFCstimulation “tapered off” after 14 days, and HDRS scores essentially returned to baseline. Avery et al.(42) followed-up on a patient who showed a robust response to rTMS (at 3 weeks post-treatment, thepatient had an HDRS score of 0, and at 1 year post-treatment she continued to rate herself as very muchimproved). Kimbrell et al. (57) noted that most patients with an initially robust response to rTMS withone stimulation frequency tended to have worse depression when they were crossed over to treatmentwith the other frequency. It was also noted that 1 patient who showed a partial response to rTMSsustained this response for 6 weeks; however, it is unclear if the patient received rTMS during this follow-up period. Finally, Padberg et al. (58) reported that 1 patient with a very robust response to rTMS (adecrease in the 21-item HDRS score from 47 to 7) maintained this response at 2 months follow-up.

Holtzheimer et al. (10) acknowledged that the studies included in the analysis differed from one anotheron multiple design parameters. In fact, when studies were segregated into groups with homogenousdesign characteristics so that a correlation with effect size could be calculated, the groups were too smallto allow meaningful analysis. The authors stated that certain design characteristics (stimulation frequency,intensity, and number of sessions) were analyzed individually and showed no significant correlation witheffect size.

According to Holtzheimer and colleagues the mean effect size statistic, which expresses the differencebetween treatment and control in terms of a pooled SD, does not clearly address the clinical significanceof rTMS in the treatment of depression. Many studies of rTMS have revealed statistically significantantidepressant effects, but these effects were usually modest. Of note, none of the studies in the meta-analysis have demonstrated a mean decrease of more than 50% in HDRS scores in the rTMS group.Overall, only 22% of the patients treated with rTMS across all of the included studies showed a more than50% decrease in HDRS scores, compared with 7.9% of patients treated with placebo.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 46

Table 8: Number of Responders (>50% Decrease in HDRS Score) by Study*†Study rTMS†

(n/N)Placebo(n/N)

Pascual-Leone et al. 4/17 0/17

Pascual Leone et al. 0/17 0/17

George et al. 1/12 0/12

Avery et al. 1/4 0/2

Klein et al. 17/35 8/32

Loo et al. 0/9 0/9

Kimbrell et al. 0/13 0/3

Kimbrell et al. 1/10 0/3*

Padberg et al. 0/6 0/6

Padberg et al. 0/6 0/6

Berman et al. 1/10 0/10

Eschweiler et al. NA NA



Garcia-Toro et al. 5/17 1/18

Avery et al. 2/7 1/8

Overall 41/183 (22%) 10/127 (7.9%)

† HDRS represents Hamilton Depression Rating Scale; rTMS, repetitive transcranial magneticstimulation

*Used with permission from the authors; Holtzheimer PE, III, Russo J, Avery DH. A meta-analysis of repetitive transcranial

magnetic stimulation in the treatment of depression. Psychopharmacology Bulletin 2001; 35(4):149-169. Incorporates erratum

reported in Psychopharmacology Bulletin 2003, Spring; 37(2): 5. (10)

In the study with the largest individual effect size, (40) patients in the rTMS group had a mean post-treatment 25-item HDRS score of 23.2, despite a mean drop of 14 points. Two studies reported on apatient with remission (defined as a post-treatment HDRS score <8) following rTMS that persisted for atleast 2 months in 1 study (58) and for 1 year in the other. (42) The studies did not report the necessaryfollow-up data to determine the overall duration of any antidepressant effects of rTMS.

Holtzheimer et al. (10) suggested that the patients included in these studies had such severe and/ortreatment-resistant depression that little improvement could have been expected. They also suggested thatrTMS in less severely depressed or less treatment-resistant patients might result in more substantialantidepressant effects. Klein et al. (5) assessed patients who were not treatment resistant and whoreceived rTMS. They found one of the largest overall drops in HDRS scores and reported the largestresponse rate (49%) compared with other studies. However, the placebo group also showed significantimprovement and had a 25% response rate.

Holtzheimer et al. said they were unable to explain why their results showed that rTMS is an effectivetreatment for depression although many of the included studies did not show this. They suggested that byusing a random-effects model, the heterogeneity among studies was explained statistically, but notclarified. They concluded, “rTMS has real antidepressant effects that can be large at times but aregenerally modest.” However, they did not clarify the clinical versus statistical significance.

Limitations of their study are similar to those in Martin et al., (3) McNamara et al., (37) and Kozel andGeorge. (8)

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 47

Alberta Heritage Foundation for Medical Research

In May 1999, the commentary from a technology scan of rTMS by the Alberta Heritage Foundation forMedical Research (38) stated:

“Use of rTMS to treat depression is based on potential to replace some ECT treatments currently used forseverely depressed patients. The technology is in the early states of assessment. Efficacy is notestablished. Longer term data, including comparison with other treatments, are needed.”

Summary of Medical Advisory Secretariat Review

The Medical Advisory Secretariat searched MEDLINE and EMBASE after the literature search cutoffdate for the most recent systematic review, from June 2001 to April 2004, for articles comparing rTMSwith alternative treatments (including ECT). Additionally, the literature was searched from April 2002 toApril 2004 for articles that compared rTMS with a placebo. This search yielded 383 studies of which 13met the inclusion criteria. The quality of the included articles is presented in Table 9.

Table 9: Quality of EvidenceStudy Design Level of

EvidenceNumber of

Eligible Studies

Large RCT, * systematic reviews of RCT 1

Large RCT unpublished but reported to an internationalscientific meeting

1(g)*

Small RCT 2 11

Small RCT unpublished but reported to an internationalscientific meeting

2(g)

Non–RCT with contemporaneous controls 3a 1

Non–RCT with historical controls 3b

Nonrandomized study presented at internationalconference

3(g)

Surveillance (database or register) 4a

Case series (multisite) 4b

Case series (single site) 4c 1

Retrospective review, modeling 4d

Case series presented at international conference 4(g)

*RCT refers to randomized controlled trial; g, grey literature

Update of rTMS versus ECT

O’Connor et al.(11) compared the effects of rTMS (n=14) and ECT (n=14) on mood and cognition inpatients with MDD (Level 3a evidence). All patients met DSM-IV criteria for MDD. Only patients withpretreatment HDRS scores of 18 or higher were included. Patients enrolled in the rTMS protocolunderwent at least a 2-week washout of all psychotropic drugs and were considered “medication free” atthe time rTMS was initiated. However, patients who received ECT continued to take medication;therefore, they received ECT as an add-on treatment. Exclusion criteria were as follows:

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 48

! Psychosis! Acute suicidality! Other current Axis I diagnoses in DSM-IV! Known central nervous system pathology! Pacemakers! Electronic or metallic implants! Severe cardiac pathology! Personal or first-degree family history of a seizure disorder! Inability to give informed consent

There were no statistically significant between-group differences for age, education, baseline memoryperformance, and estimates of verbal IQ. However, the groups differed in their levels of baselinedepression. Before treatment, patients in the rTMS group had a mean HDRS score of 29 compared withpatients in the ECT group who had a mean HDRS score of 39 (P=.001).

ECT (right unilateral) was conducted 3 times per week. The number of sessions varied according toclinical response (range, 6–12). The dosage intensity was 2.5 times the patient’s seizure threshold.Testing of ECT patients was conducted a minimum of 2 hours after treatment to minimize the effects ofanesthesia and post-ECT confusion (range 2–4 hours).

rTMS was administered in daily sessions of 1600 stimuli in 20 trains of 8-second duration with 24-secondintertrain intervals. Stimulation parameters were 10 Hz at an intensity of 90% of the motor threshold. Afocal 70 mm double cone coil was centered over the LDLPFC based on distance from the motor cortex.rTMS sessions, 5 per week, occurred for 2 weeks.

Patients were tested on 3 occasions. Baseline testing was done on the first day of treatment with ECT orrTMS. The second test was at the end of the treatment course. For patients receiving ECT, the end oftreatment varied according to clinical outcome. It ranged from 2 to 4 weeks (6–12 sessions) after the firsttreatment session. The end of rTMS treatment was fixed by the research protocol. Patients were testedafter the 10-day trial of rTMS (2 weeks) without regard to their clinical response. The third test was 2weeks after the final ECT or rTMS treatment. For rTMS, it occurred 4 weeks after the first rTMStreatment. For ECT, it happened 4 to 6 weeks after the initial ECT. A research assistant blinded to thehypotheses, but not to treatment allocation, did the testing.

Statistical Analysis

Baseline group differences on mood ratings and cognitive tasks were compared using unpaired t tests.Treatment-related differences were analyzed according to a 2x3 repeated measure analysis of variance(ANOVA). Between-subject factors were the 2 treatments (ECT or rTMS). The test sessions (baseline,end of treatment, and follow-up) were the within-subject factors. (11)

Mood RatingsBoth groups demonstrated reduced depression over the course of treatment, as measured by scores on theHDRS. Patients receiving ECT showed a decline in severity of depression from baseline (mean 39, SD7.25) to the end of treatment (mean 15.3, SD 11.7; no P value provided). At the 2-week follow-up, thesepatients continued to show a reduction in depression (mean 20.4, SD 9.5). Patients receiving rTMS had amodest reduction in severity of depression from baseline (mean 29.33, SD 4.90) to end of treatment(mean 25.6, SD7.7, no P value provided). This was also seen at the 2-week follow-up session (mean 24.8,SD 9.5, no P value provided). None of the participants in the rTMS group demonstrated a 50% reductionin depression severity on the HDRS.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 49

Figure 6: Severity of Depression: Mean Score on the Hamilton Depression Rating Scale.From O’Connor et al.(11)

The repeated-measure ANOVA indicated that there was a significant effect of treatment session onchanges in depression levels (P<.01), but there were no significant differences between groups (P>.05).There was, however, a significant interaction between the treatment session and treatment group withrespect to changes in levels of depression (P<.01).

Working Memory – Letter Numbering (LN) Sequencing

Comparisons were based on 13 ECT and 14 rTMS patients (1 missing due to a scheduling conflict).There was no difference between the groups at baseline (ECT mean, 10.92, SD 2.49; rTMS mean, 10.42,SD, 3.00). At the end of ECT treatment, there was a small decline (mean, 9.23, SD, 1.83; no P valueprovided) and improvement at the 2 weeks follow-up (mean, 11.15, SD 1.46; no P value provided).Those who received ECT did not show a statistically significant difference in LN results when baselineperformance was compared directly with the 2-week follow-up results (P>.05). The patients whoreceived rTMS showed mild improvement on the LN test over all sessions (end of treatment mean, 10.71,SD, 3.83; 2-week follow-up mean, 11.14, SD, 3.08; no P values provided).

The repeated-measure ANOVA revealed a main effect of treatment session on LN (P<.05) but there wasnot a main effect of treatment group (P>.05). There was no significant interaction between treatmentsession and groups on LN (P>.05).

New Learning – Acquisition

It is assumed that 14 ECT patients and 14 rTMS patients were examined for this outcome. At baseline,both groups performed similarly (ECT mean, 43.78, SD 11.07; rTMS mean, 43.71, SD, 12.09). Patientsin the ECT group showed reduced acquisition at the end of treatment (mean, 29.14, SD 7.93) andimproved acquisition at the 2-week follow-up session (mean, 46.92, SD, 10.80). The difference betweenbaseline acquisition and performance on the acquisition task at the 2-week follow-up session was notsignificant (P>.05). Patients in the rTMS group showed similar acquisition across the test sessions (end-of-treatment mean, 43.00, SD 10.09; 2-week follow-up mean, 44.07, SD 10.43).

Repeated measure ANOVA yielded a significant main effect of treatment session (P<.01), but there wasnot a significant main effect of treatment group (P>.05). The treatment session by treatment groupinteraction was significant (P<.01).

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 50

Figure 7: New Learning: Mean Number of Words Recalled on the Rey Auditory VerbalLearning Test Over 5 trials*

*From O’Connor et al. (11)

New Learning – Retention

It is assumed that 14 ECT and 14 rTMS patients were available for this testing. The patient groups didnot differ in baseline retention (ECT mean, 8.07, SD, 4.49; rTMS mean 9.76, SD, 3.08). Those in theECT group showed reduced retention at the end of treatment (mean, 2.15, SD, 1.99) and subsequentimprovement at the 2-week follow-up (mean, 8.92, SD, 4.14). There was no statistically significantdifference for these patients when baseline performance was compared directly with the 2-week follow-up results (P>.05). Patients in the rTMS group showed stable retention across test sessions (end-of-treatment mean, 8.23, SD, 2.80; 2-week follow-up mean, 8.31, SD, 4.07).

Repeated-measure ANOVA indicated a significant effect of treatment session (P<.01) and a significanteffect of treatment group (P<.05) on retention. Repeated measures ANOVA also indicated a significantinteraction between treatment group and session (P<.01).

New Learning – Retrograde Memory

Due to scheduling conflicts, data were available for only 10 patients in the ECT group and 11 in the rTMSgroup. The groups did not differ according to baseline retrograde memory performance (ECT mean,64.30, SD, 19.4; rTMS mean, 55.63, SD, 18.12; no P value was provided). At the end of treatment,patients in the ECT group showed reduced recall (mean, 39.10, SD, 13.21) and subsequent improvementat the end of the 2-week follow-up (mean, 59.20, SD, 20.67). Patients in the rTMS group demonstratedimprovement in retrograde memory at the end of treatment (mean, 57.81, SD, 18.33) and the 2-weekfollow-up (mean 61.54, SD, 19.12).

Repeated-measures ANOVA yielded a significant main effect of treatment session (P<.01), but there wasno significant main effect of group (P>.05). A significant interaction between treatment group andtreatment session was reported (P<.01).

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 51

Figure 8: Remote Memory: Mean Number of Items Recalled From the Transient NewsEvents Test*

*From O’Connor et al. (11)

Authors’ Conclusions

! ECT resulted in a significant reduction in depressive symptoms, and this effect was sustained 2 weeksafter the end of treatment. ECT was associated with transient negative effects on some componentsof memory and persistent effects on one task of retrograde amnesia.

! For rTMS, the magnitude of therapeutic response was small, and none of the patients in this groupdemonstrated a 50% reduction in severity of depression. However, the authors concluded that rTMSdoes not adversely affect attention and memory.

Limitations

! There was no discussion of sample size requirements, calculations, or what the study was statisticallydesigned and/or powered to answer and/or not answer specifically.

! The reporting of P values was inconsistent and sporadic.! There was no discussion of how patients were allocated to treatment. The authors said that patients

referred to the ECT service or to the Laboratory of Magnetic Stimulation at Beth Israel DeaconessMedical Center were offered participation in the study. No further information was provided.

! There were differences in depression severity between the patient groups at baseline. Patients in theECT group were more depressed at baseline; however, they also showed more improvement at theend of treatment and at the 2-week follow-up than did patients in the rTMS group.

! The test for retrograde memory used in the study is sensitive to practice effects. Therefore,improvement on repeat administrations may have been caused by being previously exposed to items.The authors said, “Because only a limited number of…items were available, the same test wasadministered on all three sessions.” (11) In addition, the patient may have become more familiar withthe examiner and more relaxed in the testing situation.

! It was a short study (2 weeks follow-up) with a very small sample size.! For ECT, treatment continued until relief from depression was observed. However, for rTMS,

treatment went according to a previously established research protocol, so that treatment wasterminated after 10 days regardless of therapeutic response. Results might have been different ifrTMS was carried out according to clinical outcome rather than to the “protocol requirements.”

! Efficacy data were obtained at the end of treatment for both groups, rather than in accordance with afixed schedule.

! The treatment arms were unbalanced. In the ECT group, patients received ECT as an add-on to drugtherapy. In the rTMS group, patients received rTMS without the adjunct of drugs. O’Connor et al.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 52

(43) argued it is unlikely that the concurrent medications would have been significantly moreeffective, because a previous trial of rTMS with concurrent medication showed only discreteantidepressant efficacy.

! Randomization was not discussed.! Intent-to-treat analysis was not discussed.

In 2003, Grunhaus et al.(59) reported on an RCT of ECT (n=20) and rTMS (n=20) of patients with severeand resistant nonpsychotic depression (Level 2 evidence). All of the patients were referred for ECT bytheir treating physician after they failed at least one course of antidepressants (at adequate levels and forat least 4 weeks of treatment). Inpatients and outpatients were included. Inclusion criteria were asfollows:

! Diagnosis of MDD (unipolar) according to DSM-IV criteria. Diagnosis was reached followingdetailed and semistructured clinical interviews by senior clinicians.

! A score of 18 or more in the 17 item HDRS.! Not meeting any of the exclusion criteria stipulated in the safety guidelines for TMS and rTMS as

stated by Wasserman.! Being over 18 years of age.! MDD was not secondary to a general medical condition or substance abuse.

Exclusion criteria were any additional Axis I diagnoses, including MDD with psychosis.

Patients were evaluated at baseline, 2 weeks into treatment, and at the end of treatment with clinicalratings that included the following the following:

! 17-item HDRS! Brief Psychiatric Rating Scale (BPRS)! Global Assessment of Function Scale (GAF)! Global Depression Scale (GDR)! Pittsburgh Sleep Quality Index (PSQI)! Mini-Mental State Examination (MMSE).

Patients were assigned to rTMS or ECT based on a previously defined random list. Ratings wereperformed by trained research assistants blind to treatment modality. (This was done by hiring assistantsthat did not regularly work with the program.) Patients in both groups were progressively withdrawnfrom psychotropic medications. The tapering process was finished within 3 days of starting the study.During the study, the only medication allowed was lorazepam (up to 3 mg per day). Patients in bothgroups were required to delay ingestion of lorazepam until after their treatment for that day.

A trained psychiatrist administered rTMS 5 times per week for 4 weeks (total, 20) over the LDLPFC.Stimulation was done at 10Hz and 90% motor threshold with 1200 pulses each day (20 6-second trainswith a 30-second interval between the trains).

Treatments with ECT were continued until the treating physician considered that a therapeutic responsehad been obtained or that no further therapeutic benefit could be expected. Patients were required to haveat least 6 ECT treatments, unless the course was suspended owing to an early therapeutic response.Patients received a mean of 10.25 (SD, 3.1) ECT treatments.

Patients were randomized to either rTMS or ECT groups based on a computer-generated list. Theprimary outcome variables were treatment response and the change in the HDRS scores. Additional

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 53

outcomes variables were changes in the scores of the BPRS, GAF, GDR, PSQI, and MMSE. A samplesize calculation or justification was not reported.

Baseline ratings for most demographic and clinical variables were similar in both groups. Patients in theECT group had significantly worse scores on the BPRS (P=.036) and the GAF (P=.007).

Positive response to treatment was defined as a decrease of 50% or more in HDRS scores, or a final ratingof 10 or less on the HDRS, and a final GAF rating of 60 or more. Remission was defined as a final HDRSscore of 8 or less.

The endpoints assessed were as follows:

! Response rate! Change of scores with treatment (ANOVA). In rating scales with baseline differences between the

groups (BPRS and GAF), ANOVA with repeated measures of change scores was used.! Extent of clinical response in those patients who improved with treatment was tested by comparing

the final ratings of both groups (t test).

The overall response rate for both groups was 58% (23/40). The primary outcome variable of response totreatment was not statistically significant between ECT (12 responded, 8 did not) and rTMS (11responded, 9 did not), P>.05.

Looking at the HDRS, GDR, PSQI, and MMSE, the ANOVA with repeated measures of absolute scoresshowed a significant effect of treatment but not of group or interaction. This suggests that scores changedsimilarly with either ECT or rTMS. Identical findings were found for the ANOVA with repeatedmeasures of change scores for the BPRS and GAF.

Table 10: ANOVAs for Clinical Ratings in Patients With Major Depression Treated WithECT or rTMS, From Grunhaus et al. (59)

Reprinted from Biological Psychiatry, 53(4), Grunhaus L, Schreiber S, Dolberg OT, Polak D, Dannon PN. A randomized

controlled comparison of electroconvulsive therapy and repetitive transcranial magnetic stimulation in severe and resistant

nonpsychotic major depression, p. 324-331, Copyright 2003, with permission from the Society of Biological Psychiatry

The final scores were similar between groups, with the exception of the GAF score in which the patientswho received rTMS had higher scores. Although final GAF scores were higher in these patients, changescores (the difference between the baseline and final score) were similar in both groups (P>.05). The rateof remission was 30%, equal in both groups.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 54

Table 11: Final Ratings for Responders Onlya From Grunhaus et al.(59)

Reprinted from Biological Psychiatry, 53(4), Grunhaus L, Schreiber S, Dolberg OT, Polak D, Dannon PN. A randomized

controlled comparison of electroconvulsive therapy and repetitive transcranial magnetic stimulation in severe and resistant

nonpsychotic major depression, p. 324-331, Copyright 2003, with permission from the Society of Biological Psychiatry

The adverse effects reported by the rTMS-treated patients were mild: 3 patients had a mild headache, and2 required a benzodiazepine for sleep disturbances. No patient in the ECT-treated group had his or hercourse interrupted due to adverse effects.

The authors drew the following conclusions:

! The clinical responses to rTMS and ECT were indistinguishable, which suggests that both treatmentswere effective for severe and resistant nonpsychotic MDD. This suggestion was supported by thefindings on the primary and secondary outcomes.

! The extent of the clinical response as assessed by the final ratings of the responders to treatment onlywas similar in both groups. The GAF was higher for the rTMS-treated patients; however, when deltascores were calculated, this difference disappeared.

! The rate of remission (final HDRS <8) was 30%, equal in both groups.

Of note, Grunhaus et al. performed rTMS for up to 20 days. In many studies, rTMS has been done for 1or 2 weeks only, and some studies have applied only 80% of the motor threshold. Grunhaus andcolleagues suggested that shorter periods of stimulation or less intense paradigms of stimulation may beassociated with weaker response rates.(60)

Limitations to the study by Grunhaus et al. were as follows:

! The results apply to the short term only.! There was no masked or placebo comparison group. It is possible that the effects of rTMS could be

secondary to placebo effects or to interactions between the treating psychiatrist and patient.However, a “true” placebo rTMS has yet to be finalized because placebo positioning of rTMS coils(placed at a 45 or 90 degree angle) can create excitability changes in the cortex.

! The clinical method for determining the exact location of the LDLPFC is not ideal. Anatomicaldifferences between patients may create positioning effects that may negatively affect the outcome.Using external navigational landmarks or neuronavigational methods (e.g., MRI) may be helpful.

! The BPRS and GAF scores favoured patients in the rTMS group. The authors suggested that futurestudies might need to incorporate matching strategies using scores of depression, agitation/psychosis,and functional state.

! The power of stimulation was based on the determination of the motor threshold in each case. Thismethod may be inaccurate, especially in elderly patients, because it has been found that the scalp-to-

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 55

cortex distance increases with age especially in the frontal cortex. Therefore, studies that providestimulation based only on the motor threshold may be underpowered.

! The sample size was small, and there was no sample size calculation. The authors said that the powerof the statistics may have been insufficient.

! Studies with more thorough cognitive batteries are needed. The MMSE is a crude measure of thecognitive effects of treatment. The MMSE results were similar between the rTMS and ECT groups atbaseline and after treatment.

Dannon et al.(6) reported 3- and 6-month outcomes of a group of patients randomly assigned to ECT orrTMS (Level 2 evidence). Inclusion criteria were as follows:

! Over 18 years of age! DSM-IV diagnosis of MDD with or without psychotic features (17-item HDRS >18)! No personal or first-degree family history of seizure! No major medical, neurological, or neurosurgical disorders

Dannon et al. noted that patients diagnosed with MDD with or without psychotic features and referred toECT were randomly assigned to receive either ECT or rTMS. However, the authors did not report howmany patients were initially diagnosed with MDD and referred to ECT. Patients who responded to acourse of ECT (n=20) or rTMS (n=23) agreed to remain for follow-up at the outpatient program.Furthermore, the authors did not say how many patients did not respond to ECT or rTMS, and if all thepatients who did respond agreed to be followed up. Response was defined as having HDRS scores of 10or less, or showing a 60% drop in HDRS scores and a final Global Assessment Scale (GAS) score of 60or more. Two patients in the rTMS group dropped out of the follow-up program; reasons were notprovided.

Treatments were delivered at 90% motor threshold over the LDLPFC and administered daily for 20 days.Patients received 1200 pulses each day at 10 Hz.

To assess improvement during the treatment period, patients were evaluated with the HDRS and the GAS.The follow-up after ECT or rTMS was performed “naturalistically” with patients visiting the outpatientclinic once a month.

All patients received antidepressants, mainly selective serotonin reuptake inhibitors, at the end oftreatment.

The main outcome of interest was the presence or absence of relapse at 3 and 6 months. Relapse wasdefined as a return of depressive symptoms meting DSM-IV criteria for MDD with a HDRS score of 16 ormore points.

Results showed both groups were similar on all the parameters at the end of treatment. Over the 6months, 8 patients (4 in ECT and 4 in rTMS) relapsed. The authors acknowledged that the small samplesize made it difficult to judge whether the relapse rate (20%) is lower than that reported in other studies ofECT-treated patients. There was no statistically significant difference in the relapse rates between theECT and rTMS groups. Two patients from the ECT group, and 1 patient from the rTMS group, relapsedduring the first 3 months. By the sixth month, 2 patients from the ECT group and 3 from rTMS group hadrelapsed.

The clinical ratings of the HDRS and GAS at 3 and 6 months were comparable between the groups (Table12).

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 56

Table 12: Clinical Variables at 3 and 6 Months Follow-Up

Reprinted from Biological Psychiatry, 51(8), Dannon PN, Dolberg OT, Schreiber S, Grunhaus L. Three and six-month outcome

following courses of either ECT or rTMS in a population of severely depressed individuals--preliminary report. Biological

Psychiatry, 687-690, Copright 2002, with permission from the Society of Biological Psychiatry (6)

The limitations to the study by Dannon et al. were as follows:

! Few patients were studied.! The authors did not report how many patients were initially diagnosed with MDD and referred to

ECT. Patients who responded to a course of ECT (n=20) or rTMS (n=23) agreed to remain forfollow-up at the outpatient program. The authors did not report how many patients did not respond toECT or rTMS and if all the patients who did respond agreed to be followed-up.

! Initial baseline data for the patient groups (prior to any treatment) was not reported.! An intent-to-treat analysis was not discussed.! The follow-up period was brief.! Uncontrolled nature of the medication regimen during follow-up.! The assessment procedure was not blinded.! One-year relapse rates of patients with resistant MDD or psychotic MDD can be as high as 50%.

Dannon et al. reported a relapse rate of approximately 20%. They said that further study on this issueis warranted.

In another study, Janicak et al. (61) compared the efficacy of rTMS with ECT for patients who had majordepression and for whom ECT would be considered appropriate in a general clinical setting (Level 2evidence). Inclusion criteria were as follows:

! Aged 18 to 75 years! DSM-IV criteria for major depression (unipolar or bipolar)! Deemed clinically appropriate for a course of ECT by treating psychiatrist

Exclusion criteria were as follows:

! Serious medical conditions that would preclude ECT or rTMS! History of clinically significant substance or alcohol abuse/dependency within the previous 3 months! Women who were pregnant or of childbearing potential and not taking contraception! Intracranial metallic or magnetic implants, or a pacemaker

All of the patients in the study had a chronic illness, scored more than 20 on the HDRS, and had multiplemedication trials. Twenty-five patients were randomized either to rTMS or to ECT. One patient in theECT group withdrew from the study after receiving 3 courses of treatment and before any clinical effector assessment. One patient crossed over from ECT to rTMS (this patient “inadvertently received low-energy right unilateral ECT”). One patient withdrew from rTMS treatment after 4 sessions and before

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 57

any clinical effect or assessment. Therefore, all analyses related to treatment are based on 22 patients. Nofurther details of these patients were reported.

Following the initial randomized treatment study, patients who did not meet response criteria couldcrossover to the alternative arm. There were no differences between the rTMS and ECT treatment groupson age, number of previous hospitalizations, age at first episode, length of episode, length of medicationwashout, and baseline symptoms. For ECT, patients received up to 12 courses of treatments usingbitemporal stimulus electrode placement. For rTMS, patients underwent 10 to 20 treatment sessions.

Before treatment, 20 of the 22 patients completed a brief medication washout (mean, 4 days; SD, 3 days).There were no differences between groups in medications received before washout. No patients werereceiving depot neuroleptics. Those previously treated with fluoxetine had not received that medicationfor at least 1 month before starting the trial. Assessments comprised the 24-item HDRS, the BPRS, theYoung Mania Rating Scale (YMRS), and the CGI. Response was defined a priori as a 50% decrease inHDRS score from baseline and a total HDRS score 8 or less. Every attempt was made to minimize theuse of concomitant rescue medications.

A paired t test was used to compare baseline to end-of-treatment ratings for each group. A continuousmeasure of improvement was obtained by calculating percent change on the rating scale total scores([pretreatment – post-treatment]/pretreatment). Categorization of responders and nonresponders wasaccording to the criteria noted above.

Both the ECT (n=13, P<.000) and rTMS (n=9, P<.001) groups showed significant improvement.However, there were no significant differences between ECT and rTMS based on percent change scoresfrom baseline to end of treatment. (Table 13.)

Table 13: Mean HDRS Scores and Percent Change

Reprinted from Biololgical Psychiatry, 51(8), Janicak PG, Dowd SM, Martis B, Alam D, Beedle D, Krasuski J et al. Repetitive

transcranial magnetic stimulation versus electroconvulsive therapy for major depression: preliminary results of a randomized

trial, p. 659-667, Copyright 2002, with permission from the Society of Biological Psychiatry (61)

For the a priori outcome, there was no significant difference in response rates between the groups. (Table14)

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 58

Table 14: Number of Responders by Treatment Group

Reprinted from Biololgical Psychiatry, 51(8), Janicak PG, Dowd SM, Martis B, Alam D, Beedle D, Krasuski J et al. Repetitive

transcranial magnetic stimulation versus electroconvulsive therapy for major depression: preliminary results of a randomized

trial, p. 659-667, Copyright 2002, with permission from the Society of Biological Psychiatry (61)

No differences were observed between the study groups on the secondary measures.

There were no significant adverse events (e.g., seizure). Generally, only mild adverse effects werereported in the rTMS group. Subjectively, patients reported various effects localized to the stimulationsite, including mild pain or discomfort (n=6), feelings of warmth (n=3), a tapping sensation (n=2), andheadache (n=1). There were no serious or unexpected adverse events associated with ECT, either.Adverse effects with bitemporal ECT included short-term memory impairment, drowsiness shortly aftertreatment, and anesthesia-induced confusion. (Specific patient numbers were not reported.)

The limitations to the study by Janicak et al. were as follows:

! It had a small sample size and was a pilot study. No sample size calculation or justification wasreported. The authors said that a larger study is warranted.

! An intent-to-treat analysis was not discussed.! In a published comment to the article by Janicak et al., Kellner et al. stated that the sample size in the

study was statistically inadequate to determine equivalence of treatments. In addition, Kellner et al.questioned the remission rate in the study, as it appeared to be lower than that commonly establishedto date.

Update of rTMS: Comparisons to Placebo or Different Frequencies or Different Locations

Studies Explicitly Stating Patients Were Treatment Resistant

Fitzgerald et al.(62) conducted a double-blind randomized placebo-controlled trial (n=60) to evaluate theefficacy of high-frequency rTMS on the LDLPFC and low-frequency rTMS on the RPFC in treatment-resistant depression (Level 2 evidence). Sixty patients with treatment-resistant depression who had failedto respond to therapy with multiple antidepressant medications were divided into 3 groups of 20 that didnot differ in age, sex, or any clinical variables. All patients completed the double-blind phase.

rTMS was administered daily for 2 weeks using 20 5-second high-frequency LDLPFC trains at 10 Hz and5 60-second low-frequency RPRC trains at 1 Hz. Placebo stimulation was applied with the coil angled at45 degrees from scalp resting on the side of one wing of the coil. The main outcome of interest was thescore on the MADRS.

Patients and raters were blind to treatment, but the clinician administering rTMS was not.

After the 10th session, a blinded assessment was made, and the patients, but not the raters, were told theirtreatment group. Patients who had a reduction in MADRS score of more than 20% in the active treatmentarms could continue with the same rTMS condition for another 10 sessions. Patients who did not achievethis improvement were offered the option of crossing over to the other active treatment. Patients initiallyrandomized to placebo were subsequently randomized to 1 of the 2 active treatments after initial review.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 59

During the second phase of study, raters remained blind to treatment type. Patients were not deliberatelywithdrawn from medication before the trial, but their doses could not have changed in the 4 weeks beforebeginning the study, or during the study.

There was a significant difference between the high-frequency LDLPFC (reduction in mean score 13.5%,SD, 16.7%) and placebo (0.76%, SD, 16.2%) groups and between the low-frequency RPFC (15.0%, SD,14.1%) and placebo groups (P<.005 for all). There was no difference between the 2 treatment groups(P=.91).

Concurrent use of medication did not have a statistically significant effect on primary outcome (P=.23).

After the randomized phase of the study, 7 (11%) of the 60 patients reported site discomfort or painduring rTMS, and 6 (10%) reported a headache after rTMS. There was no difference in the incidence ofthese adverse effects (P=.08).

Twenty-nine (48%) patients correctly guessed their type of treatment before blinding was removed, 17(42%) of 40 in the active treatment group (P=.34), and 12 (60%) of 20 in the placebo group (P=.37). Thedegree of response was the main reason given for the guess.

The limitations to the study by Fitzgerald et al. were as follows:

! No a priori sample size calculation or justification was reported.! It was a short-term study. The a priori primary outcome of interest was measured after 2 weeks of

treatment.! An intent-to-treat analysis was not discussed.! Instead of “double blind,” the trial was single blind with an evaluation by external blinded assessors.! Any analyses after 2 weeks have limited validity, because patients were aware of their treatment.

In another study, Boutros et al.(63) did an RCT to examine the efficacy and safety of rTMS as anaugmentation strategy in 22 treatment-refractory patients with depression without any modifications totheir current drug therapy (Level 2 evidence).

Twenty-two patients diagnosed with MDD were recruited. Patients had to have failed 2 prior medicationattempts and have a score of at least 20 on the HDRS. Patients were assessed at days 3, 5, 6, 8, and 10. Aresearch assistant blinded to the treatment modality administered the depression score testing. Anunblinded psychiatrist administered the rTMS. The blind was broken after the 10th session. Followingcompletion of the placebo course, patients were offered open-label active rTMS. Treatment consisted of10 left-sided stimulation sessions administered over 10 consecutive weekdays. Each session consisted of20 2-second stimulation trains, with a 20 Hz frequency applied over 20 minutes and 58-second intervalsbetween trains. Stimulations were delivered at 80% motor threshold. During placebo, the coil wasangled 90 degrees to the head.

One patient dropped out of placebo rTMS group after the first session; data from that patient wasexcluded from the analysis. Twelve patients received active rTMS, and 9 received a placebo. The HDRSscores at baseline were not significantly different between the 2 groups.

Analyses included a comparison between the HDRS scores following the last treatment with baseline as acovariate (ANCOVA). No statistically significant difference between the 2 groups was found. Arepeated-measures ANOVA found the slope for depression over time did not differ significantly betweenthe 2 groups, but there was a significant time effect (P=.001).

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 60

The authors concluded, “The data provided above strongly suggest that the rTMS parameters used in thisstudy for the treatment of depression (chosen as these were the prevailing parameters at the time ofdesigning the study) in severely ill and treatment-resistant patients are not effective.”

Patients in both groups reported adverse effects (8 in active and 5 in placebo). The most frequentcomplaint was headache during or after the session. Three patients in the active and 1 in the placebogroup reported transient scalp tenderness.

The limitations to the study by Boutros et al. were as follows:

! No a priori sample size calculation or justification was reported.! The sample size used in the study was small.! It was a short-term study of 2 weeks.! An intent-to-treat analysis was not conducted.

Padberg et al.(13) conducted a parallel-design controlled study of 31 patients with MDD that waspharmacotherapy resistant (Level 2 evidence). The authors wanted to test the hypothesis that theantidepressant efficacy of rTMS is related to the stimulation intensity applied. Patients were randomizedinto a 2-week trial of LDLPFC rTMS either at 100% motor-threshold intensity (n=10), at 90% motorthreshold (n=10), or at a low-intensity placebo (n=10). Placebo was angled 90 degrees to the head.

The dose of the currently unsuccessful antidepressant treatment was kept constant for at least 3 weeksbefore rTMS. Patients were examined by a psychiatrist uninvolved in rTMS treatment and blinded to therTMS condition. A 7-point CGI severity scale was used as overall outcome measure.

No significant differences were found between the groups for baseline HDRS, MADRS, or CGI scores.One patient dropped out due to withdrawal of consent after the second rTMS session. Across thetreatment groups, depression scores significantly declined during treatment (P<.001). However, the maineffect of treatment group was not significant. Interaction of treatment group with time was significant forMADRS scores (P<.05) but not for HDRS scores.

The linear effect on the MADRS difference scores was significant (P<.05). Expressed as percentdecrease of MADRS scores, receiving the placebo yielded a 4.1% (SE 5.2) reduction, 90% motorthreshold resulted in 15.1% (SE 6.6) decrease, and 100% motor threshold reduced MADRS scores by33.2% (SE 8.9).

The linear effect on HDRS scores was not statistically significant. Percent reductions of HDRS scoreswere 7.1% (SE 5.8) after placebo rTMS, 14.9% (SE 8.9) after 90% motor threshold, and 29.6% (SE 8.7)after 100% motor threshold.

The duration of hospital stay after rTMS and the number of antidepressant trials until discharge from thehospital were retrospectively assessed based on the patients’ charts. (Table 15)

Table 15: Antidepressant Trials and Duration of Hospital Stay by Treatment GroupAfter rTMS* 100% MT* rTMS 90% MT rTMS Placebo rTMS

Antidepressant trials (No.) 1.4+0.2 1.6+0.2 3.6+0.6

Duration of hospital stay (days) 42.6+10.2 60.6+12.7 135.0+38.0

*rTMS represents repetitive transcranial magnetic stimulation; MT, motor threshold

Reprinted by permission from Neuropsychopharmcology, 27(4), Padberg F, Zwanzger P, Keck ME, Kathmann N, Mikhaiel P,

Ella R et al. Repetitive transcranial magnetic stimulation (rTMS) in major depression: relation between efficacy and stimulation

intensity., 638-645, Copyright 2002 Macmillan Publishers Ltd. Available at:.http://www.nature.com/npp/index.html

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 61

One-way ANOVA showed significant differences between groups for the duration of hospital stay(P<.05) and the number of required antidepressant trials after rTMS (P<.001).

No severe adverse effects of rTMS were observed.

The authors concluded, “The clinical improvement after rTMS significantly increased across the 3groups, with best results at MT intensity, little improvement after subthreshold stimulation and noimprovement after low intensity stimulation.”

The limitations to the study by Padberg et al. were as follows:

! No a priori sample size calculation or justification was reported.! “Small sample size.”(13)! It was a short-term study (2 weeks).! No intent-to-treat analysis was discussed.! The authors examined the use of rTMS in patients with MDD who were pharmacotherapy resistant.

However, one of the secondary endpoints of the study was to assess the number of antidepressanttrials patients underwent until discharge from hospital. It is unclear how they defined drug resistance.

! The authors said they “regard findings as preliminary.” Furthermore, they said, “As the hypothesizedrelationship between intensity and efficacy has major implications for the therapeutic use of rTMS,further studies are needed to prove this hypothesis and investigate rTMS over a larger range of MTrelated intensities.”

Conca et al. (64) conducted an RCT to investigate the augmentation properties of rTMS. They combinedlow and high frequencies of rTMS in 36 medicated inpatients who had severe depression (Level 2evidence). Medication conditions were defined using the classification of Thase and Rush. (27) Allpatients had to be classified at stage 4 of treatment resistance, indicating a failure to respond to 2 differentadequate monotherapy trials of medications with different pharmacological profiles and a failure torespond to a second augmentation strategy. For inclusion into the study, a minimum HDRS score of 24had to be achieved.

Psychiatrists blinded to treatment methods administered the 21-item HDRS 1 day before the firsttreatment, 1 day after treatment and 1 day after completion of the entire rTMS course. The CGI scale wasadministered 1 day after rTMS.

Patients were randomly assigned to one of 3 rTMS treatment modalities while on stable drugs for 5consecutive days at 1 session per day. The group protocols were as follows:

Group 1 (n=12)

! 110% motor threshold, 10 Hz, 10 trains, train duration 10 seconds, each with a train interval of 60seconds over the LDLPFC. Over the RDLPFC: 110% motor threshold at 1 Hz, 1 train at 300seconds.

Group 2 (n=12)

! Only the LDLPFC was stimulated at 110% motor threshold, 10Hz, 10-second train durationalternating with 110% motor threshold, 1 Hz, 30-second train, with an interval of 6 seconds for 10times per session.

Group 3 (n=12)! Standard stimulation over the LDLPFC using 110% motor threshold, 10 Hz, 13 trains, and 10-second

train duration.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 62

Therapeutic outcome was based on CGI scores. Patient response was defined as achieving at leastmoderate improvement (CGI improvement score >4) and being no more than mildly depressed (CGIseverity score <4).

There were no statistically significant differences in clinical outcome between the groups. None of thedemographic, illness, diagnosis, or co-diagnosis-related data revealed any influence on the response rateexcept for handedness: right-handed patients showed a weak statistical tendency to greater therapeuticresponse (nonresponders versus responders, P<.08).

No seizures were observed in any of the patients. Seven (19.1%) of the 36 patients experienced a mildheadache during the first session. The headaches remitted spontaneously.

The limitations to the study by Conca et al. were as follows:

! No a priori sample size calculation or justification was reported.! The sample size was small.! “Preliminary findings”. (64)! There was no placebo group.! Conca et al. was the only study identified in the updated Medical Advisory Secretariat literature

search that fully defined “medication resistance” according to a detailed classification systemdeveloped by Thase and Rush. (27) (All patients had to be classified at “stage 4” of treatmentresistance, indicating a failure to respond to 2 different adequate monotherapy trials of medicationswith different pharmacological profiles, and a failure to respond to a second augmentation strategy.)

Update of rTMS: Comparisons to Placebo or Different Frequencies or Different Locations

Studies Not Explicitly Stating Patients Were Treatment Resistant, and/or Using rTMS as Add-On

Treatment

Hausmann et al. (66) conducted a single-centre, prospective, double-blind placebo-controlled add-on trial(n=41) to assess if bilateral rTMS is superior to unilateral rTMS and if there is a “speeding up” effect inthe add-on group compared with the group receiving antidepressants alone (Level 2 evidence).

Forty-one medication-free patients with MDD without psychotic features admitted to a psychiatric unitwere consecutively randomized into 3 groups. Group A1 (n=12) received unilateral active stimulation(20 Hz, 100% motor threshold, 10 trains of 10-second duration with a 90 second intertrain interval) ofhigh-frequency rTMS over the LDLPFC and subsequent placebo low-frequency rTMS over the RDLPFC.Group A2 (n=13) received simultaneous bilateral active stimulation of high-frequency rTMS over theLDLPFC and low-frequency RDLPFC rTMS (1 Hz for 10 min, 120% motor threshold). Group C (n=13)received bilateral placebo stimulation. rTMS was administered on 10 consecutive workdays. The optimalLDLPFC and RDLPFC positions were determined by three-dimensional MR imaging.

All patients received rTMS on 10 consecutive workdays. Antidepressants were started on the first day ofstimulation and were maintained throughout the stimulation period. Dosage remained constantthroughout the trial. At entry, patients underwent a 5 x half life washout period. Patients were evaluatedby blinded trained psychiatrists using the 21-item HDRS and the BDI on days 0, 1, 3, 5, 7, 10, 14, and 28.

Of the 41 patients recruited, 38 completed the 2-week protocol. At baseline, no significant differences inHDRS and BDI scores were observed among the 3 groups or between the pooled treatment groups (A1and A2) and the placebo group.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 63

There were no statistically significant differences between the 2 active-treatment groups for HDRS andBDI scores over the course of treatment (days 7, 14, and 28). Groups A1 and A2 were pooled forcomparison with Group C. At days 14 and 28, there were no statistically significant differences betweenrTMS (A1 and A2) and controls (Group C) in mean percentage decrease of the HDRS total score and theBDI.

When testing the time course of the outcome variables HDRS and BDI (days 0, 7, 14, 28) by repeated-measures ANOVA, there was a significant effect of time on HDRS (P<.001) and BDI (P<.001), but therewere no significant group differences for a group by time interaction.

The limitations to the study by Hausmann et al. were as follows:

! No a priori sample size calculation or justification was reported.! Antidepressant regimens were variable.! The authors said, “Three patients, each per group, terminated the study prematurely.” No further

details were given about the withdrawals, nor was using intent-to-treat analysis discussed .! It was a short-term study. Duration of treatment was 10 days, and outcome was measured up to 28

days from baseline.! Instead of being “double blind,” the trial was single blind with an evaluation by external blinded

assessors

Hoppner et al. (67) compared the clinical effects of 2 different stimulation procedures with placebostimulation as add-on treatments in patients with depressive disorders (Level 2 evidence). Thirty patientswith depression were recruited. Each received an antidepressant in a constant dose over 2 weeks beforeand during the stimulation period. Patients were randomly allocated to receive high-frequency LDLPFC(20, 20 Hz trains of 2-second duration with an intertrain interval of 60 seconds), low-frequency RDLPFC(2, 1 Hz trains of 60-second duration with an intertrain interval of 3 minutes), or placebo stimulation on10 out of 12 days (2 weeks with 5 sessions each week). Ten patients were in each group. Placebostimulation consisted of the same conditions as the 20 Hz rTMS, except that the coil was placed at a 90-degree angle to the head.

Severity of depression was assessed by the 21-item HDRS and the BDI. The rater was a psychiatristblind to the stimulation procedure. Clinical response was defined as at least 50% improvement frombaseline scores (HDRS, BDI) from pre to post-treatment assessment.

Twenty-nine of the 30 patients initially included in the study completed the treatment phase. One patientfrom the high-frequency treatment group refused to continue after 6 days because of insufficienteffectiveness and headache. The other 29 patients did not report adverse effects.

Only 1 of the patients was classified as a responder according to both BDI and HDRS score criteria.

Treatment response according to HDRS

Five patients in the 20 Hz group were HDRS responders, compared with 3 patients in the 1 Hz group and5 patients who were placebo stimulated. The average reduction of the HDRS baseline score was 61.8%.

HDRS scores were significantly reduced among the 20 Hz group (day 5, P=.03; end of treatment, P=.015)and the placebo stimulation group (day 5, P=.017; end of treatment, P<.001), but they were notsignificantly reduced in the 1 Hz group.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 64

Treatment response according to BDI

Two of the 9 patients treated by 20 Hz rTMS were “responders” based on the BDI-score criterion. Onepatient given treatment with 1 Hz rTMS “responded”. Two placebo-stimulated patients “responded.” Inthe 2 stimulation groups, reduction of BDI scores was observed after 5 days (20 Hz, day 5, P=.008, end oftreatment, P=.011; 1 Hz, day 5, P=.039, end of treatment P=.029). For the placebo group, improvementwas statistically significant only at the end of treatment (P=.005).

The limitations to the study by Hoppner et al. were as follows:

! No a priori sample size calculation or justification was reported.! There was no discussion of using intent-to-treat analysis. One patient from the high-frequency group

refused to continue after 6 days because of insufficient effectiveness and headache.! The Authors noted: (67)

! “Preliminary and explorative comparison study.”! “Small sample size”! The enhanced placebo effect of rTMS was due to its “impressive name, its ability to cause

involuntary movements as if by magic, its discomfort, and its bulky and sophisticated lookingequipment.”

! “Results of preliminary data points to the necessity of further research to be able to answer thestill open questions regarding stimulation procedures of rTMS, location of stimulation and of thenumber of treatment sessions.”

Nahas et al. (12) examined the safety, feasibility, and potential efficacy of using TMS to treat thedepressive symptoms of bipolar affective disorder (BPAD) (Level 2 evidence). Twenty-three patientswith BPAD (12 BPI depressed state and 9 BPII depressed state, 2 BPI mixed state) were enrolled.Patients were assigned using “an urn randomization based on age and gender” to receive daily LDLPFCrTMS (5 Hz, 110% motor threshold, 8 seconds on, 22 seconds off over 20 min) or placebo (coil angled 45degrees off head) each weekday morning for 2 weeks. Blinded assessments on the HDRS and YoungMania Rating Scale (YMRS) were obtained weekly. Patients with persistent depression could takecarbamazepine or valproate, but the dose had to be stable for 2 weeks prior to beginning treatment. Allother psychotropic medications (especially antidepressants) were tapered over a 2-week washout period(longer for fluoxetine). Patients taking lithium or lamotrigine were excluded.

The primary outcome variable was percentage change in HDRS at 2 weeks compared with day 1 oftreatment (clinical response defined as >50% decline in HDRS or a score of <10). Following the last dayof the 2-week period, the blind was broken for each patient. Patients initially randomized to placebo wereoffered the option of 2 weeks of active treatment using the same parameters. Patients who responded toeither the active or later open TMS phase were offered the option of weekly maintenance rTMStreatments over the next year.

Eleven patients received rTMS. All patients guessed their status based on their clinical response (allresponders guessed they were receiving active TMS and all clear nonresponders guessed placebo). Noadverse cognitive effects of the TMS occurred as measured by subjective complaints. There were nodropouts. No patients stopped the study due to hypomania or mania, and active rTMS treatment did notcause a statistically significant within-group increase on the YMRS (P=.49).

In the active rTMS group, 4of the 11 patients were considered responders. In the placebo group, 4 of the12 patients were responders. Each group had one patient who was a “remitter.” There was no significantdifference between the 2 groups in HDRS change from baseline over the 2 weeks (P=.83). The mean

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 65

percent change in HDRS was 25% (SD, 32%) for the active rTMS group and 25% (SD, 31%) for theplacebo rTMS group.

The limitations to the study by Nahas et al. were as follows:

! No a priori sample size calculation or justification was reported.! The sample size was small, and it was a pilot study. The authors said, “Due to the small numbers,

limited conclusions can be made from this result…”(12)! It was a short-term study. The treatment administration (and total study duration) was 2 weeks.! There was a high response to placebo.

Schule et al. (68) conducted an open trial over 2 weeks to determine if antidepressant pharmacotherapycan stabilize clinical improvement after rTMS (administered without any concurrent drugs) in 26 patients(Level 4 evidence). rTMS treatment consisted of 10 to 13 sessions, 10 Hz, 15 trains (each 10 secondswith 30-second intertrain intervals), LDLPFC at 100% motor threshold. Patients were followed-upduring standardized antidepressant pharmacotherapy with mirtazapine for a further 4 weeks. Severity ofdepression was assessed using the 21-item HDRS. HDRS ratings were obtained before rTMS treatment(day 0), after 1 week (day 7), and after 2 weeks (day 14). Raters were not involved in administeringrTMS. Response to rTMS was defined as a reduction of at least 50% of the HDRS score after 2 weeks ofrTMS compared to baseline. An overall response (rTMS followed by mirtazapine treatment, week 0–6)was defined as a decrease of at least 50% in HDRS score after 6 weeks compared to baseline. Remissionwas defined as a HDRS score of 9 or less after 2 or 6 weeks.

Ten (39%) out of the 26 patients responded to rTMS, as indicated by at least a 50% reduction in theirHDRS scores. Six (23%) of the patients were remitters (HDRS score <9). During subsequentantidepressant treatment, response and remission rates were further increased: after week 6, 20 (77%) ofthe patients achieved clinical remission.

The differences in the HDRS scores between rTMS responders and nonresponders became significant(P<.05) after 1 week of rTMS monotherapy and were observed up to the second week of mirtazapinetreatment. After 3 weeks of drug therapy, there were no more significant differences between rTMSresponders and nonresponders. Of the nonresponders to rTMS, 69% (11/16) converted into 6-weekresponders.

rTMS responders and nonresponders did not differ in the severity of their depressive symptoms atbaseline, number of depressive episodes, number of failed antidepressant trials during the current episode,and duration of the current episode. Week 6 responders and nonresponders were comparable in baselineHDRS scores and number of depressive episodes. However, week 6 nonresponders were characterized bya significantly higher number of failed antidepressant trials before entering the study (P=.025) and asignificantly longer duration of the current episode (P=.037), compared with week 6 responders.

A significant deterioration of depressive symptoms occurred between the last rTMS treatment and thefirst administration of mirtazapine in rTMS responders (P=.002), but not in rTMS nonresponders(P=.375). There was an overall low but significant correlation (P=.025) between worsening on the HDRSscore and duration of treatment interruption. The deterioration in rTMS responders was reversible inmost cases: 9/10 rTMS responders were stabilized during subsequent mirtazapine treatment (weeks 3–6).One rTMS responder became worse during pharmacotherapy.

The limitations to the study by Schule et al. (68) were as follows:

! No a priori sample size calculation or justification was reported.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 66

! There was no control group.! It was an open-study design.! Half of the patients also received lithium, carbamazepine, or neuroleptics.

Herwig et al. (69) investigated the efficacy of neuronavigated rTMS that was guided according to theprefrontal metabolic state determined by positron emission tomography (PET). A double-blindrandomized placebo-controlled study design (n=25) was used. Thirteen patients received rTMS, and 12patients received placebo rTMS (Level 2 evidence).

Prior to rTMS, PET scans were obtained. In order to state that a DLPFC was hypometabolic, a PET scanhad to show at least 5% lower activity in the mean value compared to the contralateral hemisphere. Inaddition, the mean values of the region of interest in the slices of interest on both sides had to besignificantly different in a paired t test. When these criteria were fulfilled, the site with the lowermetabolism was stimulated in the active treatment group. If no difference was detected, patients wereassigned alternating to either a left- or a right-sided stimulation.

A statistical parametric mapping analysis of the PET scan was performed for all patients at the end of thestudy (since according to the authors, this technique was methodologically established at the end of thestudy). However, for the last 3 patients of the study, parametric mapping analysis was performed prior tothe active stimulation for determination of the stimulation site replacing the region of interest analysis. In4 patients assigned to placebo stimulation, PET scans were unavailable.

Stimulation parameters were 15 Hz at 110% motor threshold. A neuronavigational system (where the coilis navigated according to individual anatomy visualized by MR imaging) was used to place the magneticcoil above each individual’s selected cortical region (active treatment: DLPFC; placebo treatment:midline parieto-occipital; intensity 90% of motor threshold). Double blinding was defined as neither theraters nor the patients being informed about the stimulation condition.

rTMS was administered as an add-on to drugs. Patients had to have been on stable antidepressantmedication for at least 3 weeks prior to stimulation onset. However, in 6 patients, the stimulation wascommenced on the day of onset of a new antidepressant medication. Furthermore, patients werepermitted to be prescribed other drugs in a “naturalistic manner,” such as low dose hypnotics, low doseolanzapine as antidepressant augmentation or lithium. Depression-related symptoms were rated with theBDI, HDRS, and MADRS. Responders were defined by a 50% reduction in the mean HDRS andMADRS ratings. Ratings were performed 5 times:

! Before stimulation! After 4 stimulations! After 7 stimulations! At the end of the stimulation sessions! In responders, 2 weeks after the stimulation sessions

The initial rating scores did not differ between the placebo and active-stimulation groups. There weresignificant differences between the placebo and active stimulation groups in terms of the relative changesin scores (at the end of stimulations compared with the initial scores normalized to 100%), in percent inHDRS (P=.002) and MADRS (P<.001), but not for the self-rating BDI (P=.1).

Four of the 13 patients in the active treatment group responded, compared with none of the 12 patients inthe placebo group. The ratings done 2 weeks after the stimulation sessions in the 4 patients thatresponded showed a persisting effect with a mean HDRS of 48% and mean MADRS of 44% of the initialrating scores.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 67

Five of the 13 patients in the active treatment group showed a relatively lower DLPFC metabolism in theinitial PET region of interest analysis and were stimulated accordingly. Only 1 of the patients was aresponder. PET-guided stimulation revealed no difference in antidepressant efficacy compared with thenon-PET-guided stimulation (BDI, P=.9; HDRS, P=.8; MADRS, P=.7).

The post-hoc PET parametric mapping analysis revealed prefrontal hypometabolism that was not detectedin the initial region of interest analysis in 3 more patients in the active treatment group and did notconfirm the prior analysis in 1 patient. Additional testing of PET- and non-PET guided showed nostatistically significant differences (BDI, P=.9, HDRS, P=.3; MADRS, P=.7).

Patients did not report any severe adverse effects of rTMS treatment.

The authors concluded, “The principle finding of the presented study is a moderate antidepressantefficacy according to HDRS and MADRS of the neuronavigated DLPFC rTMS, which does not seem todepend on the prefrontal metabolic state.” (69)

The limitations to the study by Herwig et al. were as follows:

! No a priori sample size calculation or justification was reported.! Patients were taking a wide variety of drugs.! PET technique used by the authors was not consistent throughout the study.! It was not directly tested if the navigational approach led to a better outcome than at the traditional “5

cm rule.” In fact, the effect was not better than previously reported in earlier studies that used the “5cm rule.”

! “Small sample size.” (69)! Some authors (2) reported that rating scales based on semi structured interviews (e.g., the HDRS and

MADRS) are more susceptible to observation bias than are self-administered questionnaires like theBDI. In Herwig et al., BDI scores were not statistically different between the placebo and activetreatment groups; however, the ratings for the HDRS and MADRS were significantly differentbetween groups.

Summary of Findings

Some early meta-analyses suggested that rTMS may be effective for the treatment of MDD (fortreatment-resistant MDD or as an add-on to pharmacotherapy for patients who are not specifically definedas treatment resistant). There were, however, several crucial methodological considerations andlimitations in the included studies that were not critically assessed. These are discussed below.

More recent meta-analyses, including 2 international health technology assessments, conducted anevidence-based critical analysis of studies that assessed rTMS for MDD. The 2 most recent healthtechnology assessments (from the Oxford Cochrane Collaboration and the Norwegian Centre for HealthTechnology Assessment) concluded that there is no evidence that rTMS is effective for the treatment ofMDD, either compared with a placebo in patients with either treatment-resistant or nontreatment-resistantdepression, or as an alternative to ECT in patients with treatment-resistant depression. This is mainly dueto the poor quality of the studies to date.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 68

Major methodological limitations identified in the older meta-analyses, the recent health technologyassessments, and the more recently published trials (Level 2–4 evidence) that examined the effectivenessof rTMS in patients with MDD to date include the following:

Limitations

Small sample sizes

! Lack of a priori sample size calculation or justification.! Many of the authors from recent studies acknowledged that the small sample sizes were limitations of

their studies. This is because uncontrolled variables that may influence outcomes may not be evenlydistributed between treatment and control groups.

! For studies that compared rTMS with ECT, there was no explicit methodological discussion orconsideration of the study design for the testing of equivalence between rTMS and ECT.

! The number of patients included in studies of the efficacy of rTMS in the treatment of depression fallsshort of the number of patients registered in trials for new drug treatments. (3)

Biased randomization

! There is a lack of detailed information in the published reports on the method of allocationconcealment used.

! Many studies indicated only that they were randomized, or they only described the generationallocation sequence (e.g., with a computer). This is important, because it is impossible to determine ifa possible influence (direct or indirect) existed in the allocation of the patients to different treatmentgroups. For example, this may happen if the patients who are most likely to respond are includedonly the in the active treatment arm. This can influence the results of the studies by overestimating apossible effect of treatment.

! Regression to the mean occurs whenever a nonrandom sample is selected from a population and 2imperfectly correlated variables are measured, such as 2 consecutive blood pressure measurements.(45) In the systematic review by the Cochrane Collaboration, the mean baseline depression values inmost of the studies were higher in the treatment group than in the control group. The authors said,“Although these differences were not statistically significant at the level of each individual study,they would have introduced a potential bias within the meta-analysis of pooled data by accentuatingthe tendency for regression to the mean of the more extreme values.” (3) If the patients who are mostlikely to respond (i.e., the sickest patients) are included only in the active treatment arm, then it caninfluence the final results of the studies by overestimating a possible effect of treatment.

Instead of being “double blind,” the trials were single blind with an evaluation by external blinded

assessors

! Double blinding means the participants do not know if they are receiving the treatment of interest or aplacebo, and the investigator assessing the patients does not know if the patients are receiving thetreatment of interest or a placebo.

! The people who administer rTMS cannot be blinded as to whether they are administering the activetreatment or a placebo intervention.

! There is also the potential for patients to guess which treatment they receive. In Berman et al., (40)patients deduced their treatment group in 10 of 15 cases, whereas the evaluators deduced the patienttreatment group in 12 of 15 cases.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 69

Patient variability between studies

! In some studies, the authors said that patients were “medication resistant,” but the definition ofresistant, if provided, was inconsistent or unclear. Some studies described medication resistant asfailing at least one trial of drugs during the current depressive episode. It is unclear if medicationresistance included antidepressants only or combinations of antidepressants plus any other drugaugmentation strategy or strategies (such as neuroleptics, benzodiazepine, carbamazepine, or lithium).

! In the updated Cochrane systematic review, Martin et al. (3) reported that in 7 of the 14 studies, thepatients were described as medication resistant (having failed at least one trial of dugs during thecurrent depressive episode), but in some of these studies drugs were continued, and in other studies,drugs were not continued.

! Conca et al. (65) was the only study identified in the updated Medical Advisory Secretariat literaturesearch that fully defined medication resistance according to a detailed classification system developedby Thase and Rush. (27) All patients had to be classified at “stage 4” of treatment resistance,indicating the failure to respond to 2 different adequate monotherapy trials of medications withdifferent pharmacological profiles, and the failure to respond to a second augmentation strategy.

! Padberg et al. (13) examined the use of rTMS in patients with MDD who were pharmacotherapyresistant. However, one of the secondary endpoints of the study was to assess the number ofantidepressant trials patients underwent until discharge from hospital. It is unclear how they defineddrug resistance specifically.

! The potential for concurrent medications (in both treatment and control arms) alone or in combination(e.g., antidepressants and/or lithium and/or neuroleptics and/or benzodiazepine and/orcarbamazepine) to interfere with the performance of the rTMS procedure cannot be ruled out.

! There was patient variability in the studies. Some had unipolar depression, and some had bipolardepression. Some were inpatients; others were outpatients. Some had psychotic symptoms, whereasothers had none. They also differed as to their levels of chronicity.

Dropouts or withdrawals

! Some studies reported that patients dropped out of the study, but provided no further details.! An intent-to-treat analysis was not discussed in any of the trials.! This is important because ignoring patients who drop out of a trial can bias the results, usually in

favour of the intervention. It has been reported that patients who withdraw from trials are less likelyto have taken the treatment, and more likely to have missed their interim checkups and to have hadadverse effects when taking the treatment, compared with those patients who do not withdraw. (1)

! The standard practice is to analyze the results of RCTs on an intent-to-treat basis. This means that alldata on patients originally allocated to the intervention arm of the study (including patients whowithdrew before the trial finished and those who did not take the treatment) should be analyzed alongwith data on the patients who followed the trial protocol. This means patients who withdrew from theplacebo arm of the trial should be analyzed with the patients who continued with placebo treatmentuntil the end of the trial.

Measurement of treatment outcomes using scales or inventories

! The most common scale, the HDRS, is based on a semistructured interview. Some authors (2)reported that rating scales based on semistructured interviews are more susceptible to observation biasthan are self-administered questionnaires like the BDI. Martin et al. (3) argued that the lack ofconsistency in effect as determined by the 2 scales (a positive result after 2 weeks of treatment asmeasured by the HDRS and a negative result for the BDI) makes definitive conclusions about thenature of the change in the mood of patients impossible.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 70

! Martin et al. (3) also suggested that, because of difficulties interpreting results from psychometricscales, (4) and the subjective or unstable character of MDD, other, more objective, outcome measuressuch as readmission to hospital, time to hospital discharge, time to adjunctive treatment, and time offwork should be used to assess the effectiveness of rTMS for depression. Padberg et al. (13) examinedduration of hospital stay and number of antidepressant trials until discharge from hospital in 31 drug-resistant patients who received rTMS or placebo. However, these were secondary endpointsretrospectively assessed from the charts of the patients with drug-resistant depression.

Placebo effect

! Many studies reported response rates in patients who received placebo treatment. For example, Kleinet al. (5) reported a placebo group response rate as high as 25%.

! It is possible that patients receiving placebo rTMS receive a small dose of magnetic energy that mayalter their depression.

Short-term studies

! In the studies, patients received rTMS treatment for 1 to 2 weeks.! Most studies followed-up patients for 2 to 4 weeks post-treatment. Dannon et al. (6) followed-up

patients who responded to a course of ECT or rTMS up to 6 months; however, the assessmentprocedure was not blinded, the medication regimen during follow-up was not controlled, and initialbaseline data for the patient groups were not reported.

! The long-term effectiveness of rTMS for the treatment of depression is unknown.! The long-term use, if any, of maintenance therapy is unknown.! The cost-effectiveness of rTMS for the treatment of depression is unknown. The lack of long-term

studies makes doing a cost-effectiveness analysis difficult.

Complexity of possible combinations for administering rTMS makes comparison of like versus like

difficult

! Martin et al. (3) categorized the 3 major variations in administration methods (localization on theskull, frequency, and duration of treatment period). In the majority of included studies, rTMS wasapplied to the LDLPFC, but Wasserman and Lisanby (7) stated that the method for precisely targetingthe stimulation in this area is unreliable.

! It is unknown if the LDLPFC is the optimal localization for treatment.! Further differences in rTMS administration include number of trains per session, duration of each

train, and motor threshold.

Clinical versus statistical significance

! Several meta-analyses and individual studies indicated that the degree of therapeutic changeassociated with rTMS across studies was relatively modest. (8-11).

! Conventionally, an accepted reduction in depression (i.e., response) is considered a 50% reduction inthe Hamilton Depression Rating Scale. Some studies may have observed a significantly reduceddepression rating; however, many did not demonstrate a 50% reduction. (11-13) Therefore, fewpatients in these studies would meet the standard criteria for response. (9)

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 71

Clinical/methodological diversity and statistical heterogeneity

! Clinical diversity among studies in a systematic review is defined as variability in the types ofparticipants, interventions, and outcomes studied. (16) Methodological diversity is defined asvariability in trial design and quality. (16) Statistical heterogeneity is defined as variability in thetreatment effects being evaluated in the different trials and is a consequence of clinical and/ormethodological diversity. (16)

! In the Norwegian health technology assessment, Aarre et al. (14) stated that a formal meta-analysis was not feasible because the studies varied too much in design, in the way that rTMSwas administered, and in patient characteristics. They noted that the quality of the study designswas poor. The 12 included studies had small samples, and highly variable inclusion criteria andstudy designs. The patients were often insufficiently characterized as to previous history,diagnosis, treatment history, and treatment setting. In addition, many studies stated that thepatients were treatment resistant without any clear criteria for such a designation. Without thisinformation, Aarre et al. suggested that the interpretation of the results is difficult and thegeneralizability is questionable. They concluded that rTMS cannot be recommended as astandard treatment for depression. “More, larger and more carefully designed studies are neededto demonstrate convincingly a clinically relevant effect of rTMS.” (14)

! In the Cochrane Collaboration systematic review, Martin et al. (3;15) stated that the complexityof possible combinations for administering rTMS makes comparison of like versus like difficult.The chi-square test is a statistical test for heterogeneity; the observed treatment effects beingmore different from each other than one would expect due to random error (or chance) alone. (16)However, the chi-square test must be interpreted with caution because it has low power in the(common) situation of a meta-analysis when the trials have small sample sizes or are few innumber. This means that while a statistically significant result may indicate a problem withheterogeneity, a nonsignificant result must not be taken as evidence of no heterogeneity.

! Despite not finding statistically significant heterogeneity, Martin et al. reported that the overallmean baseline depression values for the severity of depression were higher in the treatment groupthan in the placebo group. (3;15) Although these differences were not significant at the level ofeach individual study, they may have introduced potential bias within the meta-analysis of pooleddata by accentuating the tendency for regression to the mean of the more extreme values.Individual patient data from all the studies were not available; therefore, an appropriateadjustment according to baseline severity was not possible. Martin et al. concluded that thefindings from the systematic review and meta-analysis provide insufficient evidence to suggestthat rTMS is effective in the treatment of depression. Moreover, there were several confoundingfactors (e.g., definition of treatment resistance) in the included studies signifying, “The rTMStechnique needs more high quality trials to show its effectiveness for therapeutic use.” (3;15)

Economic Analysis

Literature Review

No economic analyses of rTMS for the treatment of depression were identified in the literature search.

Ontario-Based Economic Analysis

For Ontario, an expert consultant estimated about 6% to 7% of the population experienced an episode ofmajor depression the last year, and about 0.8% of the population has had a treatment resistant depression

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 72

in the past year. Of these, 80% would not be considered for electroconvulsive therapy (ECT), the goldstandard, due to the following considerations:

! Anesthetic contraindications! Unavailability of ECT! Unavailability of inpatient facilities! Request alternative antidepressant treatment

About 10% would be eligible and would accept a course of treatment in a year. Therefore about 1,800patients may receive ECT in a year. It is estimated that about 10% of these patients may have alsoreceived ECT in the past, leaving around 1,500 new patients who may have received ECT in a year.

According to Provider Services Branch of the Ministry of Health and Long-Term Care, the number ofECT procedures for the fiscal year 2002/2003 was as follows:

! Inpatient: 8,973 services! Outpatient: 5,058 servicesThe data was extracted using the following criteria:

! Fee-for-service claims only.! Ontario registered physicians only.! The data is for the physician who performed the therapy. Anesthetist claims were excluded.

According to the manufacturer, pricing for an rTMS device is as follows (in Canadian currency):

! Devices: $34,000 to $74,000 including an integral computer and software. For the treatment ofdepression, pricing is at the high end of the range.

! Coils: $6,000 to $10,000 each, and users usually have 2 or more coils per device. They are replaced atintervals, usually every 12 to 24 months, depending on usage. Note that their cost is not included inthe device price.

! Other accessories: $7,500 for cables, carts, power transformers, flexible arms for holding coils –with the purchase of a new device.

! Installation and training: $2,000; additional training days are $1,000. Offsite training costs (e.g.,travel to another site for training) are the responsibility of the purchaser

A private clinic that treated 80 patients over 1.5 years estimated that 1 machine could be used to treatabout 13 patients per day. Accordingly, the coils required replacement 5 to 10 times per year. (As morepatients received treatment, more coils required replacement.)

A technician can administer rTMS to a patient; however, a physician is required to be in close proximity(“on the floor”) when a patient receives treatment.

Existing Guidelines for Use of Technology

The American Psychiatric Association Practice Guideline For The Treatment of Patients With MajorDepressive Disorder, 2000 (70) does not mention of rTMS (or TMS) for the treatment of depression.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 73

The Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety Treatmentspartnered to produce clinical guidelines for psychiatrists for the treatment of depressive disorders in 2001.(71) They said:

“Potential clinical uses include the treatment of medication-refractory patients (perhaps in place of ECT) orbecause of its rapid onset of effect, to hasten clinical response in conjunction with antidepressants. There isstill however, no clinical consensus about the optimal parameters of treatment including frequency andanatomic location of stimulation. Most of the positive results have not yet been replicated, the follow-upperiods have been short and there are no long term or maintenance studies.

“Transcranial magnetic stimulation…are promising new biological treatments but there is too littleevidence to warrant recommendations for general clinical use (Level 2 and 3 evidence).”

The Royal Australian and New Zealand College of Psychiatrists in October 2003 (72) produced a positionstatement. A compilation of quotations taken from that report is listed below.

“rTMS presents the RANZCP with a unique situation. The Therapeutic Goods Administration (TGA) inAustralia and Medsafe in New Zealand assess new medications with respect to both safety and efficacybefore they are accepted for use in the community. However, TMS machines are classified as ‘listable’electromedical devices and, under current legislation, these bodies would not assess their efficacy. … “It istherefore important that the RANZCP accepts the responsibility for making recommendations concerningthe use of rTMS in clinical psychiatry and for monitoring such use.”

“On the basis of currently available data it is reasonable to conclude that rTMS has antidepressant efficacywhich may be clinically significant in at least a subgroup of depressed patients. Further studies are requiredto explore the question of the robustness of the clinical response and to identify those patients who arelikely to respond and to determine the most appropriate treatment parameters and site of application. Givenits favourable safety profile it is reasonable therefore to recommend that rTMS should be available tocertain patients in the clinical setting, outside of research, subject to the conditions outlined below.”

“Patients for whom rTMS might be offered outside a research protocol include:a) those suffering from Major Depression (DSM-IV) who have failed or who are intolerant of other

suitable treatments.b) previous responders to rTMS who have relapsed and are not eligible for an existing research

protocol.c) patients whose clinical presentation suggests that ECT is indicated, but who prefer to try rTMS

before ECT, or for whom ECT might present an unusually high risk.”

“Patients with a history of epilepsy or with surgically implanted metal in the head or neck should not haverTMS.”

“In view of the absence of efficacy and safety data in pregnancy, pregnant women should not have rTMSoutside of a properly conducted and ethically approved clinical trial.”

“In view of the paucity of information relating to the use of TMS in patients under the age of 18, TMSshould only be used outside of an ethically approved clinical trial after careful evaluation of the individualsituation by an appropriate child and adolescent service.”

“Until further data are available, for psychiatric illnesses other than depression rTMS should only be usedwithin an approved research protocol.”

“Patients having rTMS in the clinical setting should sign an appropriate consent form for the treatment. Theconsent form should detail the possible side effects and adverse events, including the possibility of seizuresand the induction of mania. The consent form should inform the patient that the potential benefits of rTMS

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 74

in depression may be limited, that it may not work for a particular individual, and that the most efficaciousmanner of administering rTMS has not yet been established.”

“It is recommended that rTMS should not be an office based procedure, but should only be performed in ahospital setting such as an academic unit or tertiary referral unit or in other hospital based units, such as in aprivate psychiatric hospital, provided that a protocol for the use of rTMS outside research has beendeveloped by an interested and properly trained psychiatrist or group of psychiatrists who undertake tosupervise and regulate the administration of rTMS in that hospital or clinic. Such a protocol should beapproved by an appropriate local body such as the Medical Advisory Committee or Ethics Committee orsimilar. Medical staff and resuscitation equipment such as oxygen and a simple ventilation apparatusshould be at hand in the event of a seizure.”

“rTMS is considered to be a medical procedure and should only be administered by a medical practitioneror by trained nursing staff who are under the supervision of a medical practitioner. Personnel administeringrTMS should be adequately trained in first aid and resuscitation to deal with an unexpected seizure.”

“Psychiatrists who are intending to administer rTMS, either in the clinical or research setting, should beproperly trained in the theory and technique of the treatment and the safe operation of TMS devices.”

“Although it is reasonable for certain patients to have access to rTMS outside of research for the treatmentof depression, it is recognised that as a treatment in psychiatry rTMS is in the early stage of developmentand that much research is required to establish its place in the management of psychiatric illness. For thisreason it is envisaged that for the most part, rTMS in Australia and New Zealand should continue to bedone within a research protocol. In any event, it is important that clinical information about the usefulnessand safety of rTMS is collected. Centres who wish to use rTMS should register their interest with theRANZCP, through the Committee for Psychotropic Drugs and Other Physical Treatments. Basic efficacyand safety data should be collected by each centre, regardless of whether patients are being treatedclinically or in a research trial. These data should then be forwarded to the Committee, at least annually, toenable a form of centralized monitoring of rTMS practice and outcomes in Australia and New Zealand. It isparticularly important that any adverse events, such as seizure or the induction of mania, is reported to theCommittee without delay.”

The guidelines of the National Institute for Clinical Excellence (NICE), in the United Kingdom, 2003,(73) does not mention rTMS (or TMS) for the treatment of depression.

The Beyondblue Guidelines for Treating Depression in Primary Care in Australia, 2002, (74) does notmention rTMS (or TMS) for the treatment of depression.

On the National Guideline Clearinghouse Web site (www.guideline.gov) (May 11, 2004), there were noguidelines identified specific to the treatment of depression with TMS.

The International Society for Transcranial Stimulation (ISTS) Consensus Statement on Managing theRisks of rTMS. (Adopted by ISTS Consensus Committee July, 2002) (75) said:

“Those who administer rTMS should be trained as “first responders” in order to render appropriate care inthe event of seizure.

rTMS should be performed in a medical setting with appropriate emergency facilities to manage seizuresand their consequences. Patients and research subjects should be continuously monitored during theadministration of rTMS for signs of epileptic activity or other adverse effects by a trained individual,according to criteria established in the clinical or experimental protocol. This monitoring may includeelectrophysiological recording and/or visual inspection.

http://www.guideline.gov/

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 75

During the informed consent process, patients and study participants should be informed of the risk ofseizure and its possible medical and social consequences.

The dosage of rTMS should generally be limited by published safety guidelines (e.g., Wassermann, ClinNeurophysiol, 1998;108:1 or any subsequent updates). If there is a compelling scientific or clinical reasonto exceed such guidelines, the rationale for doing so should be considered carefully, documented and thepatients or study participants should be informed that they may be at higher risk for seizure.

The long-term risks of rTMS are not known. However, the limited data available at this time (2002) fromrepeated application of high intensity, time-varying magnetic fields to humans, as in magnetic resonanceimaging, do no suggest that they are significant.

The use of rTMS should comply with regulations put forward by local regulatory bodies, medicalprofessional organizations, and medical licensing boards.”

Ongoing Trials

In addition to the ongoing trial of rTMS compared with ECT in the United Kingdom, 2 trials comparingrTMS with a placebo for the treatment of major depression are underway. Neuronetics, a manufacturer ofTMS technology, is sponsoring a multicentre RCT (76) of 286 patients with treatment-resistant majordepression who receive either active rTMS or placebo rTMS. Patients will undergo 30 outpatienttreatment sessions of about 45 minutes each over a 6-week period.

The National Institute of Mental Health is sponsoring a trial of rTMS for major depression (GrantNumber 5R01MH062154-03). (77) Eighty-six drug-free patients with MDD who have failed at least 2trials of antidepressant medication will be studied. Patients will be randomized to either active LDLPFCor placebo LDLPFC rTMS. Each patient will receive 10 sessions with 32 trains per session over 2 weeks.Blind assessment will take place before the first rTMS session, after the fifth and 10th sessions. and 1 and2 weeks post-treatment. In the second phase of the study, responders will be placed on maintenanceantidepressant medication 2 weeks after the last rTMS session and evaluated at 1 to 6 months after the lastrTMS session. The project was reported to have started August 15, 2000 and ended July 31, 2004. (77)

Appraisal

Policy Considerations

Patient outcomes

Potential advantages of rTMS compared with ECT for treatment-resistant MDD are as follows:

! No general anesthesia! Outpatient procedure! Lower energy is required. Hair, skin, and skull are not good electrical conductors; therefore, to reach

brain tissue, large currents must pass through skin-surface electrodes during ECT. However, the skulland other tissues are more “transparent” to the magnetic field created by a TMS coil; therefore, lowerenergy is needed to alter neuronal activity. (32) In addition, “The magnetic field can be highlyfocused, thereby reducing the side effects caused by the large currents that probably flow diffuselythrough neuronal structures during ECT.” (32)

! No social stigma of having to receive ECT (35)! Specific targeted stimulation

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 76

! No convulsion requirement as part of procedure! Minimal adverse effects such as mild headache and discomfort at the site of stimulation! No known adverse effects on cognition! A potential advantages of rTMS as an add-on treatment is hastening of the clinical response in

conjunction with antidepressants.! The long-term effectiveness of rTMS for severe depression is unknown.! The use, if any, of continued maintenance therapy is unknown.! Long-term pragmatic patient outcomes, such as time to further treatment, time to adjunctive therapy,

time off work, readmission to hospital, or hospital discharge, are unknown.

Demographics

! For Ontario, an expert consultant estimated that about 6% to 7% of the population has experienced anepisode of major depression the last year. About 0.8% of the population has had treatment-resistantdepression in the past year. Of these, 80% would not be considered for ECT, the gold standard, due tothe following:

! Anesthetic contraindications! Unavailability of ECT! Unavailability of inpatient facilities! Request alternative antidepressant treatment! About 10% would be eligible for, and accept a course of, treatment in a year. Therefore, about 1,800

patients may receive ECT in a year. It is estimated that about 10% of these patients may have alsoreceived ECT in the past, leaving around 1,500 new patients who may have received ECT in a year.

Diffusion

! In the United States, rTMS for treatment of depression is not approved for clinical use by the UnitedStates Food and Drug Administration.

! In the United States, insurers such as Aetna, Blue Cross Blue Shield Georgia, and the Regence Groupconsider TMS investigational for the treatment of major depression. (78-80)

! In the United Kingdom, a large RCT examining rTMS versus ECT for treatment-resistant depressionis expected to be published in mid 2005.

! In 2003, Agence d'evaluation des technologies et des mode d'intervention en sante (AETMIS) inQuebec stated that TMS appears to be promising as an ECT substitute technology; however,according to the current state of knowledge, TMS is considered experimental. (81)

! A private rTMS clinic based in Western Canada recently opened a new clinic in Toronto to treatpatients with major depression. The clinic charges about $4,000 (Cdn) for a course of treatment(about 5, 1-hour sessions per week for 4 weeks).

Cost

According to the manufacturer, pricing for an rTMS device is as follows (in Canadian currency):! Devices: $34,000 to $74,000 including an integral computer and software. For the treatment of

depression, pricing is at the high end of the range.! Coils: $6,000 to $10,000 each, and users usually have 2 or more coils per device. They are replaced at

intervals, usually every 12 to 24 months, depending on usage. Note that their cost is not included inthe device price.

! Other accessories: $7,500 for cables, carts, power transformers, flexible arms for holding coils –with the purchase of a new device.

! Installation and training: $2,000; additional training days are $1,000. Offsite training costs (e.g.,travel to another site for training) are the responsibility of the purchaser

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 77

! A private clinic that treated 80 patients over 1.5 years estimated that 1 machine could be used to treatabout 13 patients per day. Accordingly, the coils required replacement 5 to 10 times per year. (Asmore patients received treatment, more coils required replacement.)

! A technician can administer rTMS to a patient; however, a physician is required to be in closeproximity (“on the floor”) when a patient receives treatment.

Stakeholder Analysis

! If rTMS is not approved for funding, psychiatrists with an interest in administering rTMS fordepression may discontinue research.

System Pressures

! If rTMS is approved for funding, technicians or psychiatrists administering rTMS will requiretraining, which is provided by the device manufacturer.

! If rTMS is not approved for funding, hospitals may discontinue rTMS research programs indepression.

! If rTMS is approved for funding, patient volumes should be maintained at selected centres to define,improve, and refine the administration technique.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 78

Appendices

Appendix 1

Figure 1: TMS equipmentUsed with permission from Magstim Company, available at http://www.magstim-us.com

Figure 2: TMS being administered to a patient.Used with permission from From Dr. Thomas E. Schlaepfer, University Hospital Bonn; Available at:http://pni.unibe.ch/artwork/Brainweek.gif

http://www.magstim-us.com/

http://pni.unibe.ch/artwork/Brainweek.gif

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 79

Appendix 2

Figure 3: Location of prefrontal cortexUsed with permission from the Lundbeck Institute; Available at Brain Explorer:http://www.brainexplorer.org/glossary/prefrontal_cortex.shtml

Figure 4: Dorsolateral prefrontal cortex (outside view)Image provided courtesy of Amen Clinics Inc., www.amenclinics.com; Available athttp://www.brainplace.com/bp/brainsystem/prefrontal.asp

http://www.amenclinics.com/

http://www.brainplace.com/bp/brainsystem/prefrontal.asp

http://www.brainexplorer.org/glossary/prefrontal_cortex.shtml

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM

Appendix 3

Burt T, Lisanby SH, Sackeim HA. Neuropsychiatric applications of transcranial magnetic stimulation: a meta analysis. International Journal of Neuropsychopharmacology 2002;

5(1):73-103; Subject to the copyright notice provided by Cambridge University Press, Reprinted with the permission of Cambridge University Press and theauthor (9)

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 81

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 82


5(1):73-103; Subject to the copyright notice provided by Cambridge University Press, Reprinted with the permission of Cambridge University Press and the author (9)

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 83

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 84



D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 85



D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 86



D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 87



D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 88

Table 7. rTMS studies (comparator is placebo, different intensities, or different cranial locations) published from 2002 to April 2004.

Study (year,author,country)

Objective Method Results Limitations

2003Fitzgerald etal.(62)Australia

To prospectivelyevaluate the efficacyof high-frequencyLDLPFC and low-frequency RPFC intreatment resistantdepression andcompared with aplacebo-treatedcontrol group.

Double-blind randomized placebo-controlled trial.Primary outcome measured after 2 weeks treatment.Participants: 60 patients with treatment resistantdepression who had failed to respond to therapy withmultiple antidepressant medications were divided into3 groups of 20 that did not differ in age, sex or anyclinical variables. All patients completed the double-blind phase of the study.Intervention: 20, 5-second high-frequency LDLPFCtrains at 10 Hz and 5 60 second low-frequency RPRCtrains at 1 Hz applied daily for 2 weeks. Placebostimulation applied with coil angled at 45 degreesfrom scalp resting on the side of one wing of the coil.Main outcome measure: score on Montgomery-Asberg Depression Rating Scale.

Patients and raters were blind to treatment, but theclinician administering rTMS was aware of thetreatment group.

After the 10thsession, a blinded assessment was

made and the patients but not the raters wereinformed of their treatment group. Patients who had areduction in MADRS score of >20% in the activetreatment arms could continue with the same TMScondition for another 10 sessions. Patients notachieving this improvement offered option of crossingover to the other active treatment. Patients initiallyrandomized to placebo were subsequentlyrandomized to 1 of the 2 active treatments after initialreview. During 2

ndphase of study, raters remained

blind to treatment type.

Patients were not deliberately withdrawn frommedication before the trial, but their doses were notallowed to have changed in the 4 weeks beforecommencement of or during the trial.Figure-8 coil.

Significant difference in response amongthe 3 groups with a significant differencebetween the high-frequency LDLPFC[reduction in mean score 13.5%+SD16.7%]and placebo [0.76%+16.2%] groups andbetween the low-frequency RPFC[15.0%+14.1%] and placebo groups(P<.005 for all) but not between the 2treatment groups (P=.91).

Concurrent use of medication did not havea statistically significant effect on primaryoutcome (P=.23).

After phase 1, 7 (11%) of the 60 patientsreported site discomfort or pain duringrTMS and 6 (10%) reported a headacheafter rTMS. No difference n the incidenceof these adverse effects (P=.08).

29 (48%) of patients correctly guessed theirtype o f treatment before disclosure, 17(42%) of 40 in the active treatment group(P=.34) and 12 (60%) of 20 in the placebogroup (P=.37). The degree of responsewas the predominant reason given for theguess.

No a priori sample sizecalculation or justificationreported.The a priori primary outcome ofinterest was measured after 2weeks of treatment.After 2 weeks, the study is nolonger considered double blind.Any analyses after the double-blind phase of the study is limitedsince patients were aware of theirtreatment.

2004Hausmann etal.(66)Austria

To assess whetherbilateral rTMS issuperior to unilateralrTMS and that there isa speeding up effectin the add on group incomparison to the

Single centre, prospective double-blind placebo-controlled “add on” trial.41 medication free patients with MDD withoutpsychotic features admitted to a psychiatric unit wereconsecutively randomized into 3 groups.Group A1 (n=12) received unilateral active stimulation(20 Hz, 100% MT, 10 trains of 10 sec duration with a

Of 41 patients recruited, 38 completed the 2week protocol.

No significant differences between the 3groups as well as between the pooledtreatment groups (A1 and A2) and theplacebo group regarding HDRS and BDI

No a priori sample sizecalculation or justificationreported.Antidepressant regimens werevariable.Duration of treatment was 10days, outcome measured up to

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 89

usual care groupmedicated withantidepressantsalone.

90 sec intertrain interval) consisting of high-frequencyrTMS over the LDLPFC and subsequent placebo low-frequency rTMS over the RDLPFC.Group A2 (n=13) received simultaneous bilateralactive stimulation consisting of high-frequency rTMSover the LDLPFC and low-frequency RDLPFC rTMS(1 Hz for 10 min, 120% MT).Group C (n=13) received bilateral placebo stimulation.Stimulation was performed on 10 consecutiveworkdays.Antidepressants were started on the first day ofstimulation and maintained throughout the stimulationperiod. Dosage remained constant throughout thetrial. At entry patients underwent a 5 x half lifewashout period.The optimal LDLPFC and RDLPFC positions weredetermined by 3D MRI.Figure-8 coil.

scores at baseline.No significant differences between the 2active treatment groups in terms of HDRSand BDI scores over the course oftreatment (day 7, 14, and 28). Groups A1and A2 were pooled for comparison toGroup C.

At day 14 and 28 there was no statisticallysignificant difference between rTMS (A1and A2) and controls (Group C) in meanpercentage decrease of the HDRS totalscore and the BDI.

When testing the time course of theoutcome variables, HDRS and BDI (days 0,7, 14, 28) by repeated measures ANOVA,there was a significant effect of time onoutcome variables in both groups, whereasthere were no significant group differencesin terms of a group by time interaction. Thesize of the interaction term for the HDRSamounted to 2.8 (95% CI -2.8 to 8.5) forday 14 versus baseline, and 3.0 (95% CI -3.8 to 9.8) for day 28 versus baseline,where a positive value indicates a favour forgroup A1+A2. The corresponding valuesfor BDI were 5.0 (95% CI -3.2 to 13.2) and5.7 (95% CI -3.8 to 15.0) respectively.

28 days from baseline.

2003Hoppner etal.(67)Germany

To compare clinicaleffects of 2 differentstimulationprocedures withplacebo stimulation asadd on treatments inpatients withdepressive disorders.

30 depressed patients. Every patient received anantidepressant in a constant dose over 2 weeksbefore and during the stimulation period. Patientswere randomly allocated to receive high-frequencyLDLPFC (twenty 20 Hz trains of 2 sec duration withintertrain interval of 60 sec), low-frequency FDLPFC(two 1 Hz trains of 60 sec duration with an intertraininterval of 3 minutes) or placebo stimulation on 10 outof 12 days (2 weeks with 5 sessions each week). Tenpatients were included in each group.

Placebo stimulation consisted of same conditions asthe 20 Hz rTMS except that the coil was placed at a90 degree angle to the head.

Severity of depression was assessed by HDRS (21items) and BDI. The rater was a psychiatrist who wasblind to the stimulation procedure.

Clinical response was defined as >50% improvement

29/30 patients initially included in the studycompleted the treatment phase. Onepatient from the high-frequency treatmentgroup refused to continue after 6 daysbecause of insufficient effectiveness andheadache. The other 29 patients did notreport adverse effects.

5 patients in the 20Hz group wereresponders compared to 3 patients in the 1Hz group and 5 patients who were placebostimulated. Average reduction of baselinescore was 61.8%.

Only one of the patients was classified asresponder according to both BDI and HDRSscore criteria.

HDRS scores significantly reduced amongthe 20 Hz group (day 5 P=.03; end of

No a priori sample sizecalculation or justificationreported.Authors stated:1) “Preliminary and explorativecomparison study”.2) “Small sample size”3) Enhanced placebo effect ofrTMS due to its “impressivename, its ability to causeinvoluntary movements as if bymagic, its discomfort, and itsbulky and sophisticated lookingequipment.”4) “Results of preliminary datapoints to the necessity of furtherresearch to be able to answer thestill open questions regardingstimulation procedures of rTMS,location of stimulation and of the

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 90

of baseline scores (HDRS, BDI) between pre and posttreatment assessments.

Figure-8 coil.

treatment P=.015) and placebo stimulationgroup (day 5 P=.017; end of treatmentP<.001) but was not statistically significantin the 1 Hz group.

2/9 patients treated by 20 Hz were“responders” based on BDI. One patientfrom 1 Hz “responded”. Two placebostimulated patients “responded”.

Within the 2 stimulation groups, reductionwas observed after 5 days (20 Hz day 5,P=.008, end of treatment, P=.011; 1 Hz day5, P=.039, end of treatment P=.029). Forthe placebo treatment group, improvementwas statistically significant only at the endof treatment (P=.005).

number of treatment sessions. “

2003Nahas et al.(12)United States

To determine thesafety feasibility andpotential efficacy ofusing TMS to treat thedepressive symptomsof bipolar affectivedisorder (BPAD).

23 depressed BPAD patients (12 BPI depressed stateand 9 BPII depressed stated, 2 BPI mixed state) wereenrolled.Patients assigned using “an urn randomization basedon age and gender) to receive daily LDLPFC rTMS (5Hz, 110% MT, 8 sec on, 22 sec off over 20 min) orplacebo (coil angled 45 degrees off head) eachweekday morning for 2 weeks.Blinded HDRS and Young Mania Rating Scales(YMRS) obtained weekly.Patients could take carbamazepine or valproate buteth dose had to be stable for 2 weeks prior tobeginning treatment with persisting depression. Allother psychotropic medications (especiallyantidepressants) were tapered over a 2 weekwashout period, longer for fluoxetine). Patients onlithium and lamotrigine were also excluded.Primary outcome variable: percentage change inHDRS at 2 weeks compared with day 1 of treatment(clinical response defined as >50% decline in HDRSor <10).Following last day of the 2 week period, the blind wasbroken for each patient. Patients initially randomizedto placebo were offered the option of 2 weeks ofactive treatment at the same parameters. Treatmentresponders to either the active or later open TMSphase were offered the option of weekly maintenanceTMS treatments over the next year.

Figure-8 coil.

11 patients received rTMS.All patients guessed their status based ontheir clinical response (all respondersguessed they were receiving active TMSand all clear nonresponders guessedplacebo).No adverse cognitive effects of the TMS asmeasured by subjective complaints.No drop outs from the study.No patients stopped the study as a result ofhypomania or mania and active rTMS didnot cause a statistically significant withingroup increase in the YMRS (P=.49).

4/11 active TMS patients were responders.4/12 placebo TMS patients wereresponders. Each group had one “remitter”.There was no significant differencebetween the 2 groups in HDRS changefrom baseline over the 2 weeks (P=.83).Mean % change in HDRS was 25% (SD,32%) for the active TMS and 25% (SD,31%) for the placebo TMS.

No a priori sample sizecalculation or justificationreported.Small sample size.Two weeks duration.Only 2 week drug washoutperiod.High placebo response.

2002Boutros et

“To provide efficacyand safety data for

22 patients diagnosed with MDD. Patients had tohave failed 2 prior medication attempts. A score of at

One patient dropped out of placebo rTMSafter the first session – data from that

No a priori sample sizecalculation or justification

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 91

al.(63)United States

use of subthresholdrTMS as anaugmentation strategyin treatment refractorydepressed patientswithout anymodifications on theircurrentpharmacologicaltherapy in a double-blind randomizedfashion.”

least 20 on the HDRS was required. Patientsrandomized into either placebo or active rTMS.Patients assessed at days 3, 5, 6, 8, and 10. Aresearch assistant blinded to the treatmentadministered the depression score testing. Unblindedpsychiatrist administered the rTMS. Blind brokenfollowing treatment #10.

Following completion of the placebo course, patientswere offered open label active rTMS.

Treatment consisted of 10 left sided stimulationsessions administered over 10 consecutiveweekdays. Each session consisted of 20, 2secstimulation trains, with a 20 Hz frequency applied over20 min with 58 second intervals between trains.Stimulations were delivered at 80% MT.

Figure-8 coil. During placebo, the coil was angled 90degrees to the head.

patient was excluded from the analysis. 12patients were randomized to receive activerTMS and 9 to placebo.There was no statistically significantdifference between HDRS scores atbaseline between the 2 groups.

Analyses performed included a comparisonbetween the HDRS scores following the lasttreatment with baseline as a covariate(ANCOVA). No difference between the 2groups was found.

A repeated measures ANOVA found thatthe slope associated with depression overtime did not differ significantly between the2 groups but a significant time effect(P=.001) occurred.

Patients in both groups reported adverseeffects (8 in active and 5 in placebo). Mostfrequent complaint was headache during orafter the session. 3 patients in the activeand 1 in the placebo reported transientscalp tenderness.

reported.

“Sample size used in the studywas small”.Two week randomized duration.

2002Padberg etal.(13)Germany

To test the hypothesisthat antidepressantefficacy of rTMS isrelated to thestimulation intensityapplied.

Parallel design controlled study of 31 patients withMDD who were pharmacotherapy resistant prior torTMS.Patients randomized into a 2 week trial of LDLPFCrTMS either at 100% MT intensity (n=10) at 90% MT(n=10) or at a low intensity placebo condition (n=10).One patient dropped out due to withdrawal of consentafter the second rTMS session. The dosage of thecurrent unsuccessful antidepressant treatment waskept constant for at least 3 weeks prior to rTMS.Patients were examined by a psychiatrist uninvolvedin rTMS treatment and blinded to the rTMS condition.Placebo was angled 90 degrees to the head.A 7 point clinical global impression (CGI) of severityscale was used as overall outcome measure.

Figure-8 coil.

No significant differences were foundbetween the groups for baseline HDRS,MADRS or CGI scores.

Across treatment groups, depressionscores significantly declined during rTMS(P<.001). The main effect of treatmentgroup was not significant. Interaction oftreatment group with time was significantfor MADRS scores (P<.05) but not forHDRS scores.

The linear effect on MADRS differencescores was significant (P<.05). Expressedin percent decrease of MADRS scores,placebo yielded a 4.1% (SE 5.2) reduction,90% MT resulted in 15.1% (SE 6.6)decrease and 100% MT reduced MADRSscores by 33.2% (SE 8.9)

The linear effect on HDRS scores showedwas not statistically significant. Percentreductions of HDRS scores were 7.1% (SE5.8) after placebo rTMS, 14.9% (SE 8.9)after 90% MT and 29.6% (SE 8.7) after

No a priori sample sizecalculation or justificationreported.“Small sample size”.“Regard findings as preliminary”.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 92

100% MT.One way ANOVA showed significantdifferences between groups for bothduration of the hospital stay (P<.05) and thenumber or required antidepressant trialsafter rTMS (P<.001).

No severe adverse effects of rTMS wereobserved.

2002Conca et al.(65)Austria

To investigate theaugmentationproperties of rTMScombining low andhigh frequencies.

Recruited 36 severely depressed medicated inpatients. Medication conditions defined using theclassification of Thase and Rush (1995) – all patientshad to be classified at stage 4 of treatment resistanceindicating the failure to respond to 2 differentadequate monotherapy trials of medications withdifferent pharmacological profiles and the failure torespond to a 2

ndaugmentation strategy.

Psychiatrists blinded to treatment methods completedthe 21 item HDRS 1 day before the first treatment and1 day after completion and 1 day after completion ofthe rTMS course. For inclusion, a minimum score of>24 had to be achieved.

Clinical Global Improvement (CGI) completed 1 dayafter rTMS. Patients remained on the last prescribedpharmacotherapy.

Patients randomly assigned to 3 different rTMStreatment modalities while on stable drugs for 5consecutive days.

rTMS administered on 5 consecutive days at 1session/day.Group 1 (n=12) = 110% MT, 10Hz, 10 trains, trainduration 10 seconds, each with a train interval of 60seconds over the LDLPFC. Over the RDLPFC:110% MT at 1 Hz, 1 train at 300 seconds.Group 2 (n=12) = only the LDLPFC was stimulated at110% MT, 10Hz, 10 second train duration alternatingwith 110% MT, 1 Hz, 30 second train, with an intervalof 6 seconds for 10 times/session.Group 3 (n=12) = standard stimulation over LDLPFCusing 110% MT, 10 Hz, 13 train and 10 second trainduration.

Therapeutic outcome measurement was based onCGI scores. Patient response was defined asachieving at least moderate improvement (CGIimprovement score >4) and being no more than mildly

No statistical differences in clinical outcomebetween the groups.

None of the demographic, illness,diagnosis, or co-diagnosis related datarevealed any influence on the response rateexcept for handedness; right handedpatients showed a weak statistical tendencyto greater therapeutic response (nonresponders vs responders, P<.08).

No seizures were observed.

7/36 patients (19.1%) experienced a mildheadache during the first session whichremitted spontaneously.

No a priori sample sizecalculation or justificationreported.Small sample size“Preliminary findings”.No control group

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 93

ill (CGI severity score <4).

Figure-8 coil.

2003Schule etal.(68)Germany

To examine whetherantidepressantpharmacotherapy canstabilize clinicalimprovement afterrTMS monotherapy

26 drug-free patients.Open trial over 2 weeks10-13 sessions, 10 Hz, 15 trains (each 10 seconds)with 30 second intertrain intervals) LDLPFC at 100%MT.Patients followed-up during standardizedantidepressant pharmacotherapy with mirtazapine fora further 4 weeks.Severity of depression assessed using 21 itemHDRS. Ratings performed before rTMS treatment(day 0) and after one week (day 7) and after 2 weeksof rTMS (day 14).Raters were not involved in rTMS treatment.Response to rTMS was defined by a reduction of atleast 50% of the HDRS score after 2 weeks of rTMScompared to baseline. An overall response (rTMSfollowed by mirtazapine treatment) week 0-6) wasdefined by a decrease of at least 50% in the HDRSscore after 6 weeks compared with baseline (week 6response).Remission was defined as a HDRS score of 9 or lessafter 2 weeks or 6 weeks respectively.

10/26 (39%) of patients responded to rTMSby at least 50% reduction in the HDRS.23% (6/26) were remitters (HDRS score<9).During subsequent antidepressanttreatment, response and remission rateswere further increased: after week 6, 77%of the patients (20/26) achieved clinicalremission.The differences in the HDRS scoresbetween rTMS responders andnonresponders became significant (P<.05)after 1 week of rTMS monotherapy andwere observed up to the 2

ndweek of

mirtazapine treatment. After 3 weeks ofdrug therapy, there were no moresignificant differenced between rTMSresponders and nonresponders. 69% ofthe rTMS nonresponders (11/16) convertedinto 6-week responders.rTMS responders and nonresponders didnot differ in severity of depressivesymptoms at baseline, number ofdepressive episodes, and number of failedantidepressant trials during the currentepisode and duration of the currentepisode. Week-6 responders andnonresponders were comparable n baselineHDRS scores and number of depressiveepisodes. However, week-6nonresponders were characterized by asignificantly higher number of failedantidepressant trials before entering thestudy (P=.025) and a significantly longerduration of the current episode (P=.037)compared with week-6 responders.A significant deterioration of depressivesymptoms occurred between the last rTMStreatment and the first administration ofmirtazapine in rTMS responders (P=.002),but not in rTMS nonresponders (P=.375).An overall low but significant correlation(P=.025) between worsening on the HDRSscore and duration of treatment interruption.The deterioration in rTMS responders wasreversible in most cases: 9/10 rTMSresponders showed an at least stabilized

No a priori sample sizecalculation or justificationreported.No control group.Open study design.Half of the patients also receivedlithium, carbamazepine, orneuroleptics.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 94

course during subsequent mirtazapinetreatment (week 3-6). One rTMS responderbecame worse during pharmacotherapy.

2003Herwig etal.(69)Germany

To investigate theefficacy ofneuronavigated rTMSguided according tothe prefrontalmetabolic statedetermine by PET.

Double-blind randomized placebo controlled pilotstudy25 patients with MDD.13 patients rTMS12 patients placebo.Prior to rTMS, PET scans obtained. For stimulation,the DLPFC with lower metabolic activity compared tothe contralateral hemisphere was selected.Stimulation parameters 15 Hz, 110%MT. Aneuronavigational system (navigate the coil accordingto individual anatomy visualized by MRI) was used toplace the magnetic coil above each individualsselected cortical region (active treatment: DLPFC;placebo treatment: midline parieto-occipital, intensity90% of MT).rTMS was administered as an add-on to drugs.Depression related symptoms rated with BDI, HDRS,and MADRS scales.Responders were defined by a 50% reduction of themean of the HDRS and MADRS ratings.Double blind=neither the raters nor the patients wereinformed about the stimulation condition.Ratings performed 5 times:Before stimulationAfter 4 stimulationsAfter 7 stimulationsAt the end of the stimulation sessions andIn responders 2 weeks after the stimulationssessions.Figure-8 coil.

Severe adverse effects not observed.Initial rating scores of the placebo and realstimulated patients did not differ betweenthe groups.There were significant differences betweenthe placebo and active stimulation groups interms of the relative changes in scores (atthe end of stimulations compared with theinitial scores normalized to 100%) inpercent in HDRS (P=.002) and MADRS(P<.001) but not for the self rating BDI(P=0.1).Responder rate=4/13 in active treatmentgroup and 0/12 in the placebo group.The ratings performed 2 weeks after thestimulation sessions in the 4 respondingreal stimulated patients showed a persistingeffect with a mean HDRS of 48% and meanMADRS of 44% of the initial rating scores.Authors concluded “preliminary resultsindicate that rTMS of prefrontalhypometabolism may not be advantageousto stimulation irrespective of the metabolicstate.”

No a priori sample sizecalculation or justificationreported.Not directly tested if thenavigational approach led tobetter outcome than at the “5 cmrule”.“small sample size”

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM

References(1) Sackett DL, Haynes RB, Guyatt GH, Tugwell P. Clinical epidemiology - a basic science for clinical

medicine. London: Little Brown, 1991.(2) Hotopf M, Chruchill R, Lewis G. Pragmatic randomized controlled trials in psychiatry. Br J Psychiatry

1999; 175:217-223.(3) Martin JL, Barbanoj MJ, Schlaepfer TE, Thompson E, Perez V. Repetitive transcranial magnetic

stimulation for the treatment of depression: systematic review and meta-analysis. Br J Psychiatry 2003;182:480-491.

(4) Rosenberg R. Outcome measures of antidepressive therapy. Acta Psychiatr Scand 2000; 101:41-44.(5) Klein E, Kreinin I, Chistyakov A, Koren D, Mecz L, Marmur S et al. Therapeutic efficacy of right

prefrontal slow repetitive transcranial magnetic stimulation in major depression: a double-blindcontrolled study.[see comment]. Archives of General Psychiatry 1999; 56(4):315-320.

(6) Dannon PN, Dolberg OT, Schreiber S, Grunhaus L. Three and six-month outcome following courses ofeither ECT or rTMS in a population of severely depressed individuals--preliminary report. BiologicalPsychiatry 2002; 51(8):687-690.

(7) Wassermann EM, Lisanby SH. Therapeutic application of repetitive transcranial magentic stimulation: areview. Clin Neurophysiol 2001; 112:1367-1377.

(8) Kozel FA, George MS. Meta-analysis of left prefrontal repetitive transcranial magnetic stimulation(rTMS) to treat depression. Journal of Psychiatric Practice 2002; 8(5):270-275.

(9) Burt T, Lisanby SH, Sackeim HA. Neuropsychiatric applications of transcranial magnetic stimulation: ameta analysis. International Journal of Neuropsychopharmacology 2002; 5(1):73-103.

(10) Holtzheimer PE, III, Russo J, Avery DH. A meta-analysis of repetitive transcranial magnetic stimulationin the treatment of depression. Psychopharmacology Bulletin 2001; 35(4):149-169.

(11) O'Connor M, Brenninkmeyer C, Morgan A, Bloomingdale K, Thall M, Vasile R et al. Relative effects ofrepetitive transcranial magnetic stimulation and electroconvulsive therapy on mood and memory: aneurocognitive risk-benefit analysis. Cognitive & Behavioral Neurology 2003; 16(2):118-127.

(12) Nahas Z, Kozel FA, Li X, Anderson B, George MS. Left prefrontal transcranial magnetic stimulation(TMS) treatment of depression in bipolar affective disorder: a pilot study of acute safety and efficacy.Bipolar Disorders 2003; 5(1):40-47.

(13) Padberg F, Zwanzger P, Keck ME, Kathmann N, Mikhaiel P, Ella R et al. Repetitive transcranialmagnetic stimulation (rTMS) in major depression: relation between efficacy and stimulation intensity.Neuropsychopharmacology 2002; 27(4):638-645.

(14) Aarre TF, Dahl AA, Hohansen JB, Kjonniksen I, Neckelmann D. Efficacy of repetitive transcranialmagnetic stimulation in depression: a review of the evidence. Nordic Journal of Psychiatry 2003;57:227-232.

(15) Martin JLR, Barbanoj MJ, Schlaepfer TE, Clos S, Perez V, Kulisevsky J et al. Transcranial magneticstimulation for treating depression. Cochrane Database of Systematic Reviews 2004;(1).

(16) Cochrane Statistical Methods Group. Analysing and Presenting Results. In: Deeks J, Higgins J, AltmanD, editors. Cochrane Reviewers' Handbook 4.2.2. Oxford: Cochrane Collaboration, 2004: 68-139.

(17) Reus VI. Mental Disorders. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL,editors. Harrison's Principles of Internal Medicine. New York: McGraw-Hill, 2001: 2542-2556.

(18) Parikh SV, Lam RW and the CANMAT Depression Work Group. Clinical guidelines for the treatment ofdepressive disorders. I. Definitions, prevalence and health burden. Canadian Journal of Psychiatry 2001;46:13S-19S.

(19) Mueller TI, Leon AC, Keller MB, Solomon DA, Endicott J, Coryell W et al. Recurrence after recoveryfrom major depressive disorder during 15 years of observational followup. Am J Psychiatry 1999;156:1000-1006.

(20) Lee AS, Murray RM. The long term outcome of Maudsley depressives. Br J Psychiatry 1988; 153:741-751.

(21) Anonymous. American Psychiatric Association practice guideline for the treatment of patients withmajor depressive disorder. Am J Psychiatry 2000; 157(Suppl 4):1-45.

(22) Kennedy SH, Lam RW, Morris B, for the CANMAT Depression Work Group. Clinical guidelines fordepressive disorders. summary of recommendations relevant to family physicians. Can Fam Physician2003; 49:489-491.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 96

(23) UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders: asystematic review and meta-analysis. Lancet 2003; 361:799-808.

(24) Rose D, Wykes T, Leese M, Bindman J, Fleischmann P. Patients' perspectives on electroconvulsivetherapy: systematic review. Br Med J 2003; 326:1363-1367.

(25) National Institute of Clinical Evidence. Depression: the management of depression in primary andsecondary care. NICE guideline. Draft for Second Consultation, December 2003. 1-58. 2003.

(26) Stimpson N, Agrawal N, Lewis G. Randomised controlled trials investigating pharmacological andpsychological interventions for treatment refractory depression. Br J Psychiatry 2002; 181:284-294.

(27) Thase ME, Rush AJ. Treatment resistant depression. In: Bloom FE, Kupfer DJ, editors.Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press Ltd., 1995: 1081-1097.

(28) Chaimowitz GA, Links PS, Padgett RW et al. Treatment resistant depression: a survey of practice habitsof Canadian psychiatrists. Canadian Journal of Psychiatry 1991; 36:353-356.

(29) Nierenberg AA, White K. What next? A review of pharmacologic strategies for treatment resistantdepression. Psychopharmacology Bulletin 1990; 26:429-460.

(30) Shergill SS, Katona CLE. Pharmacological choices after one antidepressant fails: a survey of UKpsychiatrists. J Affect Disord 1997; 43:19-25.

(31) Fitzgerald PB, Brown TL, Daskalakis ZJ. The application of transcranial magnetic stimulation inpsychiatry and neurosciences research. Acta Psychiatr Scand 2002; 105:324-340.

(32) Hasey G. Transcranial magnetic stimulation in the treatment of mood disorder: a review and comparisonwith electroconvulsive therapy. Canadian Journal of Psychiatry 2001; 46:720-727.

(33) George MS, Wassermann EM, Williams WA, Callahan A, Ketter TA, Basser P et al. Daily repetitivetranscranial magnetic stimulation (rTMS) improves mood in depression. Neuroreport 1995; 6:1853-1856.

(34) Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: Report and suggestedguidelines from the International Workshop on the Safety of Repetitive Transcranial MagneticStimulation, June 5-7, 1996. Electroencephalography & Clinical Neurophysiology: Evoked Potentials1998; . 108(1):1-16.

(35) Kirkcaldie M, Pridmore S, Reid P. Bridging the skull: Electroconvulsive therapy (ECT) and repetitivetranscranial magnetic stimulation (rTMS) in psychiatry. Convuls Ther 1997; . 13(2):83-91.

(36) Dahl AA, Aarre TF, Johansen JB, Neckelmann D, Kjonniksen I. Transcranial magnetic stimulation in thetreatment of depressions. 2001. Oslo: The Norwegian Centre for Health Technology Assessment(SMM).

(37) McNamara B, Ray JL, Arthurs OJ, Boniface S. Transcranial magnetic stimulation for depression andother psychiatric disorders. Psychol Med 2001; 31(7):1141-1146.

(38) Alberta Heritage Foundation for Medical Research. Repetitive transcranial magnetic stimulation. 1999.Edmonton: Alberta Heritage Foundation for Medical Research (AHFMR).

(39) Martin JLR, Barbanoj MJ, Schlaepfer TE, Clos S, Perez V, Kulisevsky J et al. Cochrane Database ofSystematic Reviews 2004;(1).

(40) Berman RM, Narasimhan M, Sanacora G, Miano AP, Hoffman RE, Hu XS et al. A randomized clinicaltrial of repetitive transcranial magnetic stimulation in the treatment of major depression. BiologicalPsychiatry 2000; 47(4):332-337.

(41) Eschweiler GW, Wegerer C, Schlotter W, Spandl C, Stevens A, Bartels M et al. Left prefrontal activationpredicts therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) in major depression.Psychiatry Research 2000; 99(3):161-172.

(42) Avery DH, Claypoole K, Robinson L, Neumaier JF, Dunner DL, Scheele L et al. Repetitive transcranialmagnetic stimulation in the treatment of medication-resistant depression: preliminary data. Journal ofNervous & Mental Disease 1999; 187(2):114-117.

(43) GarciaToro M, PascualLeone A, Romera M, Gonzalez A, Mico J, Ibarra O et al. Prefrontal repetitivetranscranial magnetic stimulation as add on treatment in depression. Journal of Neurology, Neurosurgery& Psychiatry 2001; 71(4):546-548.

(44) GarciaToro M, Mayol A, Arnillas H, Capllonch I, Ibarra O, Crespi M et al. Modest adjunctive benefitwith transcranial magnetic stimulation in medication-resistant depression. Journal of Affective Disorders2001; 64(2-3):271-275.

(45) Morton V, Torgerson DJ. Effect of regression to the mean on decision making in health care. Br Med J2003; 326:1083-1084.

(46) National Health Service Research and Development Health Technology Assessment Programme.Clinical effectiveness and cost of repetitive transcranial magnetic stimulation versus ECT in severedepression: a multicentre randomized controlled trial and economic analysis.

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 97

http://www.hta.nhsweb.nhs.uk/projectdata/1_project_record_notpublished.asp?PjtId=1203&Search . 3-26-2004.

(47) PascualLeone A, Rubio B, Pallardo F, Catala MD. Rapid-rate transcranial magnetic stimulation of leftdorsolateral prefrontal cortex in drug-resistant depression.[see comment]. Lancet 1996; 348(9022):233-237.

(48) Speer AM, Repella JD, Figueras S, Demian NK, Kimbrell TA, Wasserman EM et al. Lack of adversecognitive effects of 1 Hz and 20 Hz repetitive transcranial magnetic stimulation at 100% of motorthreshold over left prefrontal cortex in depression. Journal of ECT 2001; 17(4):259-263.

(49) Martin JLR, Barbanoj MJ, Schlaepfer TE, Clos S, Perez V, Kulisevsky J et al. Cochrane Database ofSystematic Reviews 2004;(1).

(50) Boylan LS, Pullman SL, Lisanby SH, Spicknall KE, Sackeim HA. Repetitive transcranial magneticstimulation to SMA worsens complex movements in Parkinson's disease. Clin Neurophysiol 2001;112:259-264.

(51) Kammer T, Beck S, Thielscher A, Laubis-Herrmann U, Topka H. Motor thresholds in humans: atranscranial magnetic stimulation study comparing different pulse waveforms, current directions andstimulator types. Clin Neurophysiol 2001; 112:250-258.

(52) Pridmore S. Rapid transcranial magnetic stimulation and normalization of the dexamethasonesuppression test. Psychiatry & Clinical Neurosciences 1999; 53(1):33-37.

(53) Kozel FA, Nahas Z, DeBrux C, Molloy M, Lorberbaum JP, Bohning D et al. How coil-cortex distancerelates to age, motor threshold, and antidepressant response to repetitive transcranial magneticstimulation. Journal of Neuropsychiatry & Clinical Neurosciences 2000; 12(3):376-384.

(54) Grunhaus L, Dannon PN, Schreiber S, Dolberg OH, Amiaz R, Ziv R et al. Repetitive transcranialmagnetic stimulation is as effective as electroconvulsive therapy in the treatment of nondelusional majordepressive disorder: an open study. Biological Psychiatry 2000; 47(4):314-324.

(55) Conca A, Koppi S, Konig P, Swoboda E, Krecke N. Transcranial magnetic stimulation: a novelantidepressive strategy? Neuropsychobiology 1996; 34(4):204-207.

(56) Loo C, Mitchell P, Sachdev P, McDarmont B, Parker G, Gandevia S. Double-blind controlledinvestigation of transcranial magnetic stimulation for the treatment of resistant major depression.American Journal of Psychiatry 1999; 156(6):946-948.

(57) Kimbrell TA, Little JT, Dunn RT, Frye MA, Greenberg BD, Wassermann EM et al. Frequencydependence of antidepressant response to left prefrontal repetitive transcranial magnetic stimulation(rTMS) as a function of baseline cerebral glucose metabolism. Biological Psychiatry 1999; 46(12):1603-1613.

(58) Padberg F, Zwanzger P, Thoma H, Kathmann N, Haag C, Greenberg BD et al. Repetitive transcranialmagnetic stimulation (rTMS) in pharmacotherapy-refractory major depression: comparative study of fast,slow and placebo rTMS. Psychiatry Research 1999; 88(3):163-171.

(59) Grunhaus L, Schreiber S, Dolberg OT, Polak D, Dannon PN. A randomized controlled comparison ofelectroconvulsive therapy and repetitive transcranial magnetic stimulation in severe and resistantnonpsychotic major depression. Biological Psychiatry 2003; 53(4):324-331.

(60) Gershon AA, Dannon PN, Grunhaus L. Transcranial magnetic stimulation in the treatment of depression.Am J Psychiatry 2003; 160:835-845.

(61) Janicak PG, Dowd SM, Martis B, Alam D, Beedle D, Krasuski J et al. Repetitive transcranial magneticstimulation versus electroconvulsive therapy for major depression: preliminary results of a randomizedtrial.[see comment]. Biological Psychiatry 2002; 51(8):659-667.

(62) Fitzgerald PB, Brown TL, Marston NA, Daskalakis ZJ, De Castella A, Kulkarni J. Transcranial magneticstimulation in the treatment of depression: a double-blind, placebo-controlled trial. Archives of GeneralPsychiatry 2003; 60(10):1002-1008.

(63) Boutros NN, Gueorguieva R, Hoffman RE, Oren DA, Feingold A, Berman RM. Lack of a therapeuticeffect of a 2-week sub-threshold transcranial magnetic stimulation course for treatment-resistantdepression. Psychiatry Research 2002; 113(3):245-254.

(64) Conca A, Di Pauli J, Beraus W, Hausmann A, Peschina W, Schneider H et al. Combining high and lowfrequencies in rTMS antidepressive treatment: preliminary results. Human Psychopharmacology 2002;17(7):353-356.

(65) Conca A, Peschina W, Hausmann A, Koenig P. Combining 1-Hz and 10-Hz rTMS in the treatment ofdepressives. European Psychiatry: the Journal of the Association of European Psychiatrists 17 Suppl1:218, 2002.

http://www.hta.nhsweb.nhs.uk/projectdata/1_project_record_notpublished.asp?PjtId=1203&Search

D"E"/$/$)" 7,&0*%,&0$&' !&50"/$% ./$8F'&/$+0 L,7!.M N :0/&,$+ 2"&'/3 7"%30+'+5- (**"**8"0/ .",$"* ;<<=>=LCM 98

(66) Hausmann A, Kemmler G, Walpoth M, Mechtcheriakov S, KramerReinstadler K, Lechner T et al. Nobenefit derived from repetitive transcranial magnetic stimulation in depression: a prospective, singlecentre, randomised, double blind, sham controlled "add on" trial. Journal of Neurology, Neurosurgery &Psychiatry 2004; 75(2):320-322.

(67) Hoppner J, Schulz M, Irmisch G, Mau R, Schlafke D, Richter J. Antidepressant efficacy of two differentrTMS procedures. High frequency over left versus low frequency over right prefrontal cortex comparedwith sham stimulation. European Archives of Psychiatry & Clinical Neuroscience 2003; 253(2):103-109.

(68) Schule C, Zwanzger P, Baghai T, Mikhaiel P, Thoma H, Moller HJ et al. Effects of antidepressantpharmacotherapy after repetitive transcranial magnetic stimulation in major depression: an open follow-up study. Journal of Psychiatric Research 2003; 37(2):145-153.

(69) Herwig U, Lampe Y, Juengling FD, Wunderlich A, Walter H, Spitzer M et al. Add-on rTMS fortreatment of depression: a pilot study using stereotaxic coil-navigation according to PET data. Journal ofPsychiatric Research 2003; 37(4):267-275.

(70) Anonymous. American Psychiatric Association practice guideline for the treatment of patients withmajor depressive disorder (revision). Am J Psychiatry 2000; 157(Suppl 4):1-45.

(71) Kennedy SH:Lam RW, Cohen NL, Ravindran AV, and the CANMAT Depression Work Group. ClinicalGuidelines for the treatment of depressive disorders. IV. Medications and other biological treatments.Canadian Journal of Psychiatry 2001; 46:38S-58S.

(72) Royal Australian and New Zealand College of Psychiatrists. Transcranial Magnetic Stimulation (TMS).Position Statement # 40. www.ranzcp.org/pdffiles/posstate/ps40.pdf . 2003.

(73) National Institute of Clinical Evidence. Depression: the management of depression in primary andsecondary care. NICE guideline. Draft for Second Consulation, December 2003. 1-58. 2003.

(74) Ellis PM, Smith DAR. Treating depression: the beyondblue guidelines for treating depression in primarycare. Med J Aust 2002; 176:S77-S83.

(75) Belmaker B, Fitzgerald P, George MS, Lisanby SH, Pascual-Leone A, Schlaepfer TE et al. Managing therisks of repetitive transcranial stimulation. Cns Spectrums 2003; 8:489.

(76) ECRI. Magnetic therapy under study to treat major depression. Health Technology Forecast. 2004.(77) Avery DH. Project Title: TMS treatment of major depression. Grant Number 5R01MH062154-03.

http://crisp.cit.nih.gov . 2004.(78) Aetna. Clinical Policy Bulletin. Transcranial Magnetic Stimulation and Cranial Electrical Stimulation.

1469. 2004.(79) The Regence Group. Transcranial Magnetic Stimulation. www.regence.com/printFriendly.jsp . 2-3-2004.(80) Blue Cross Blue Shield Georgia. Transcranial magnetic stimulation as a treatment of depression and

other neuropsychiatric disorders.www.provider.bcbsga.com/provider/medpolicy/policies/behavioral_health/magnetic_stim_depress.html .6-25-2003.

(81) Agence d'evaluation des technologies et des mode d'intervention en sante (AETMIS). The use ofelectroconvulsive therapy in Quebec. 2003.

http://www.regence.com/printFriendly.jsp

http://www.provider.bcbsga.com/provider/medpolicy/policies/behavioral_health/magnetic_stim_depress.html

http://www.ranzcp.org/pdffiles/posstate/ps40.pdf

http://crisp.cit.nih.gov/

Documents

DE/$/$) 7,&0*%,&0$&’ !&50/$% ./$8F’&/$+0 1+, /3 7,&/80/ +1 !&G+, … · 2016. 3. 30. · D"E"/$/$)" 7,&0*%,&0$&’ !&50"/$% ./$8F’&/$+0 L,7!.M N :0/&,$+ 2"&’/3 7"%30+’+5-

DE/$/$) 7,&0%,&0$&’ !&50/$% ./$8F’&/$+0 1+, /3 7,&/80/ +1 !&G+, … · 2016. 3. 30. · D"E"/$/$)" 7,&0%,&0$&’ !&50"/$% ./$8F’&/$+0 L,7!.M N :0/&,$+ 2"&’/3 7"%30+’+5-